Compounds and methods of treating or ameliorating an IL-1R-mediated disease or disorder using same

ABSTRACT

The present invention provides compounds useful for treating or preventing an IL-1R-mediated disease or disorder. In certain embodiments, the disease or disorder comprises scleroderma.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of, and claims priority to,U.S. patent application Ser. No. 15/328,281, filed Jan. 23, 2017, whichis a 35 U.S.C. § 371 national phase application from, and claimspriority to, International Application No. PCT/US2015/043403, filed Aug.3, 2015 and published under PCT Article 21(2) in English, which claimspriority under 35 U.S.C. § 119(e) to U.S. Provisional Patent ApplicationNo. 62/032,668, filed Aug. 4, 2014, all of which applications areincorporated herein by reference in their entireties.

BACKGROUND OF THE INVENTION

Scleroderma, also known as systemic sclerosis, is a chronic systemicautoimmune disease that primarily affects the skin and is characterizedby hardening (sclerosis) of the skin and internal organs due to theexcessive accumulation of collagen. Further, scleroderma ischaracterized by damage to small blood vessels, activation of Tlymphocytes and production of antinuclear antibodies.

Limited scleroderma involves cutaneous manifestations that mainly affectthe hands, arms and face, with the following common manifestations:calcinosis (deposition of calcium nodules in the skin), Raynaud'sphenomenon (exaggerated vasoconstriction in the hands, with fingersundergoing white-blue-red color transitions in the cold), esophagealdysfunction (leading to difficulty swallowing), sclerodactyly (skinthickening on the fingers), and telangiectasias (dilated capillaries onthe face, hands and mucous membranes) with internal organ involvementmany years after disease diagnosis. On the other hand, diffusescleroderma progresses rapidly and is quite disabling, affecting a largearea of the skin and internal organs, such as the kidneys, esophagus,heart and/or lungs.

The prognosis is dire for limited cutaneous scleroderma patients whoescape pulmonary complications (they generally die of lung failurewithin 30 years post diagnosis), but is even worse for those with thediffuse cutaneous disease, particularly in patients who are older and/ormale. Death occurs most often from pulmonary, heart and kidneycomplications. In diffuse cutaneous disease, five-year survival is about70% and 10-year survival is about 55%.

Scleroderma is of unknown etiology, but is often thought to be anautoimmune condition. Further, strong associations between sclerodermaand certain mutations in the human leukocyte antigen (HLA) gene and/orenvironmental factors have been identified.

There are no approved treatments or cures for scleroderma itself, butindividual organ system complications may be treated. Systemicdisease-modifying treatment with immunosuppressants is often used inscleroderma. Immunosuppressants used include azathioprine, methotrexate,cyclophosphamide, mycophenolate mofetil, intravenous immunoglobulin,rituximab, sirolimus, alefacept, and the tyrosine kinase inhibitors,imatinib, nilotinib and dasatinib. Experimental therapies currentlyunder investigation include endothelin receptor antagonists, tyrosinekinase inhibitors, beta-glycan peptides, halofuginone, basiliximab,alemtuzumab, abatacept and hematopoietic stem cell transplantation.

Anakinra (KINERET®) and rilonacept (ARCALYST®) are currently undergoingclinical trials for the treatment of scleroderma. These drugs, which arelarge recombinant proteins requiring direct infusions, directly targetinterleukin 1 (IL-1) signaling by either interfering with the IL-1receptor (IL-1R) or sequestering IL-1 from the circulation. Anakinra isa human IL-1R antagonist, binding to IL-1R and blocking its binding ofIL-1α or IL-1β. Rilonacept is a dimeric protein comprising theligand-binding domains of the extracellular portions of the human IL-1Rand human IL-1R accessory protein linked to the Fc portion of humanimmunoglobulin G1 (IgG1). Rilonacept binds and neutralizes circulatingIL-1. Anakinra and rilonacept are also used in treating other autoimmunediseases such as rheumatoid arthritis, lupus, and Sjogren's syndrome.

Currently there is a critical lack of approved therapies forIL-1R-mediated diseases or disorders, such as the orphan diseasescleroderma. There is thus a need in the art for novel therapeuticcompounds that treat or ameliorate scleroderma, or a complication orsymptom thereof, in mammals. The present invention fulfills this need.

BRIEF SUMMARY OF THE INVENTION

The invention provides compound, or a salt, tautomer or solvate thereof.The invention further provides pharmaceutical compounds comprising atleast one compound of the invention.

The invention further provides a method of treating or ameliorating anIL-1R-mediated disease or disorder in a mammal in need thereof, themethod comprising administering to the mammal a therapeuticallyeffective amount of at least one compound of the invention, whereby thedisease or disorder is treated or ameliorated.

In certain embodiments, the compound of the invention is selected fromthe group consisting of:

-   (i) a compound of formula (I):

wherein in (I),

ring A is selected from the group consisting of:

wherein in ring A one occurrence of R¹ is CR⁶ and the other occurrenceof R¹ is N or CR⁷ and the furan rings are independently optionallysubstituted with R⁷;

R² is selected from the group consisting of bond, —CH₂S—, —SCH₂—,—CH₂O—, —OCH₂—, —(CH₂)₁₋₆—, arylene, heteroarylene, and combinationsthereof;

R³ is selected from the group consisting of —C₁-C₆ alkyl, —C₂-C₆alkenyl, —C₁-C₆ heteroalkyl, —(C₀-C₃ alkyl)-(C₃-C₈ cycloalkyl), —(C₀-C₃alkyl)-(C₄-C₁₀ heterocyclyl), —(C₀-C₃ alkyl)-(C₆-C₁₀ aryl) and —(C₀-C₃alkyl)-(C₅-C₁₀ heteroaryl), wherein the alkyl, alkenyl, heteroalkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl group is independentlyoptionally substituted;

R⁴ is selected from the group consisting of —C₁-C₆ alkyl, —C₁-C₆heteroalkyl, —(C₀-C₃ alkyl)-(C₃-C₈ cycloalkyl), —(C₀-C₃ alkyl)-(C₄-C₁₀heterocyclyl), —(C₀-C₃ alkyl)-(C₆-C₁₀ aryl), —(C₀-C₃ alkyl)-(C₅-C₁₀heteroaryl), —(CH₂)₁₋₃—C(═O)NH₂, —(CH₂)₁₋₃—C(═O)NHNHC(═O)R⁵,—S(CH₂)₁₋₃—C(═O)NH₂, —S(CH₂)₁₋₃—C(═O)NHR⁸, —S(CH₂)₁₋₃—C(═O)OR³ and—S(CH₂)₁₋₃—C(═O)NHNHC(═O)R⁵, wherein the alkyl, heteroalkyl, cycloalkyl,heterocyclyl, aryl or heteroaryl group is independently optionallysubstituted;

each occurrence of R⁵ is independently —C₄-C₁₀ heterocyclyl, —C₆-C₁₀aryl or C₅-C₁₀ heteroaryl, wherein the heterocyclyl, aryl or heteroarylgroup is independently optionally substituted;

each occurrence of R⁶ is independently selected from the groupconsisting of —NHR⁸, —C(═O)OH, —C(═O)OR⁸ and —C(═O)NHR⁸;

each occurrence of R⁷ is independently H, halo, —C₁-C₆ alkyl or —C₃-C₁₀cycloalkyl, wherein the alkyl or cycloalkyl group is independentlyoptionally substituted; and,

each occurrence of R⁸ is independently selected from the groupconsisting of —C₁-C₆ alkyl, —C₁-C₆ heteroalkyl, —(C₀-C₃ alkyl)-(C₃-C₈cycloalkyl), —(C₀-C₃ alkyl)-(C₄-C₁₀ heterocyclyl), —(C₀-C₃alkyl)-(C₆-C₁₀ aryl) and —(C₀-C₃ alkyl)-(C₅-C₁₀ heteroaryl), wherein thealkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groupis independently optionally substituted;

-   (ii) a compound of formula (II):

wherein in (II):

R¹ and R³ are independently selected from the group consisting of—(C₀-C₃ alkyl)-(C₆-C₁₀ aryl), and —(C₀-C₃ alkyl)-(C₅-C₁₀ heteroaryl),wherein the alkyl, aryl or heteroaryl group is independently optionallysubstituted;

R² is S, S(═O) or S(═O)₂;

R⁴ is selected from the group consisting of —(CH₂)₁₋₃C(═O)OH,—(CH₂)₁₋₃C(═O)OR⁵ and —(CH₂)₁₋₃C(═O)NHR⁵; and,

each occurrence of R⁵ is independently selected from the groupconsisting of —C₁-C₆ alkyl, —C₁-C₆ heteroalkyl, —(C₀-C₃ alkyl)-(C₃-C₈cycloalkyl), —(C₀-C₃ alkyl)-(C₄-C₁₀ heterocyclyl), —(C₀-C₃alkyl)-(C₆-C₁₀ aryl) and —(C₀-C₃ alkyl)-(C₅-C₁₀ heteroaryl), wherein thealkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groupis independently optionally substituted;

(iii) a compound of formula (III):

wherein in (III),

each occurrence of R¹ is independently N or CR⁶;

R² is selected from the group consisting of —(C₀-C₃ alkyl)-(C₄-C₁₀heterocyclyl), —(C₀-C₃ alkyl)-(C₆-C₁₀ aryl) and —(C₀-C₃ alkyl)-(C₅-C₁₀heteroaryl), wherein the alkyl, heterocyclyl, aryl or heteroaryl groupis independently optionally substituted;

R³ and R⁴ are independently selected from the group consisting of—(CH₂)₁₋₃—C(═O)OR⁵, —(CH₂)₁₋₃—C(═O)NH₂, —(CH₂)₁₋₃—C(═O)NHR⁵,—S(CH₂)₁₋₃—C(═O)NH₂, —S(CH₂)₁₋₃—C(═O)OR⁵ and —S(CH₂)₁₋₃—C(═O)NHR⁵;

each occurrence of R⁵ is independently H, —C₁-C₆ alkyl, —C₃-C₁₀cycloalkyl, —C₆-C₁₀ aryl, or heteroaryl, wherein the alkyl, cycloalkyl,aryl or heteroaryl group is independently optionally substituted; and,

each occurrence of R⁶ is independently H, halo, —C₁-C₆ alkyl, —C₃-C₁₀cycloalkyl, —C₆-C₁₀ aryl, or heteroaryl, wherein the alkyl, cycloalkyl,aryl or heteroaryl group is independently optionally substituted;

(iv) a compound of formula (IV):

wherein in (IV),

R¹ is selected from the group consisting of —(C₀-C₃ alkyl)-(C₄-C₁₀heterocyclyl), —(C₀-C₃ alkyl)-(C₆-C₁₀ aryl) and —(C₀-C₃ alkyl)-(C₅-C₁₀heteroaryl), wherein the alkyl, heterocyclyl, aryl or heteroaryl groupis independently optionally substituted;

R² is selected from the group consisting of —(CH₂)₁₋₃—C(═O)OR⁴,—(CH₂)₁₋₃—C(═O)NH₂, and —(CH₂)₁₋₃—C(═O)NHR⁴;

R³ is —C(═O)OR⁴, —C(═O)NHR⁴ or —S(═O)₂NHR⁴;

each occurrence of R⁴ is independently H, —C₁-C₆ alkyl, —C₃-C₁₀cycloalkyl, —C₆-C₁₀ aryl, or heteroaryl, wherein the alkyl, cycloalkyl,aryl or heteroaryl group is independently optionally substituted; and,

A ring is optionally further substituted;

(v) a compound of formula (V):

wherein in (V),

R¹ is selected from the group consisting of O, NH and N(C₁-C₆ alkyl),wherein the alkyl group is optionally substituted;

R² is selected from the group consisting of H and —(C₁-C₆ alkyl),wherein the alkyl group is optionally substituted;

R³ is selected from the group consisting of H, —(C₁-C₆ alkyl) and aryl,wherein the alkyl or aryl group is optionally substituted;

R⁴ is optionally substituted aryl;

R⁵ is selected from the group consisting of —CN, —C(═O)OH and—C(═O)O(C₁-C₆ alkyl), wherein the alkyl group is optionally substituted;and

R⁶ is methyl or NH₂;

(vi) the compound of formula (VI),3-(furan-2-ylmethyl)-8-(naphthalen-1-yl)-6-oxo-3,4,7,8-tetrahydro-2H,6H-pyrido[2,1-b][1,3,5]thiadiazine-9-carbonitrile:

(vii) the compound of formula (VII),6-amino-4-(2-hydroxynaphthalen-1-yl)-3-methyl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile:

(viii) the compound of formula (VIII),2-((3-cyano-4-(naphthalen-1-yl)-6-oxo-1,4,5,6-tetrahydropyridin-2-yl)thio)-N-phenylacetamide:

(ix) the compound of formula (IX), methyl6-amino-5-cyano-2-(methoxymethyl)-4-(naphthalen-1-yl)-4H-pyran-3-carboxylate:

(x) the compound of formula (X),2-amino-4-(naphthalen-1-yl)-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-carbonitrile:

(xi) a compound of formula (XI):

wherein in (XI):

each occurrence of R¹ is independently selected from the groupconsisting of H and methyl;

R² is O or —NH; and

R³ is optionally substituted phenyl or naphthyl;

(xii) a compound of formula (XII):

wherein in (XII):

R¹ is phenyl or benzyl, wherein the phenyl or benzyl group is optionallysubstituted;

R² is H or methyl; and,

R³ is optionally substituted phenyl;

(xiii) a compound of formula (XIII):

wherein in (XIII):

R¹ is optionally substituted phenyl;

R² is optionally substituted phenyl; and,

R³ is optionally substituted phenyl or heteroaryl;

and any mixtures thereof.

In certain embodiments, in (I) ring A is selected from the groupconsisting of:

In other embodiments, in (I) in ring A one occurrence of R¹ is CR⁶ andthe other occurrence of R¹ is CR⁷. In yet other embodiments, in (I) R²is selected from the group consisting of —CH₂S—, —SCH₂— and —(CH₂)₁₋₆—.In yet other embodiments, in (I) R³ is selected from the groupconsisting of —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₃-C₈ cycloalkyl, —(C₀-C₃alkyl)-(C₆-C₁₀ aryl) and —(C₀-C₃ alkyl)-(C₅-C₁₀ heteroaryl), wherein thealkyl, alkenyl cycloalkyl, aryl or heteroaryl group is independentlyoptionally substituted. In yet other embodiments, in (I) R⁴ is selectedfrom the group consisting of C₁-C₆ alkyl, —(C₀-C₃ alkyl)-(C₆-C₁₀ aryl),—(C₀-C₃ alkyl)-(C₅-C₁₀ heteroaryl), —(CH₂)₁₋₃—C(═O)NH₂,—S(CH₂)₁₋₃—C(═O)NH₂, —S(CH₂)₁₋₃—C(═O)OR³ and—S(CH₂)₁₋₃—C(═O)NHNHC(═O)R⁵. In yet other embodiments, in (I) R⁵ isC₆-C₁₀ aryl or C₅-C₁₀ heteroaryl, wherein the aryl or heteroaryl groupis independently optionally substituted. In yet other embodiments, in(I) R⁶ is selected from the group consisting of —NHR⁸ and —C(═O)NHR⁸. Inyet other embodiments, in (I) R⁷ is H, halo or C₁-C₆ alkyl, wherein thealkyl group is optionally substituted. In yet other embodiments, in (I)R⁸ is selected from the group consisting of —(C₀-C₃ alkyl)-(C₃-C₈cycloalkyl), —(C₀-C₃ alkyl)-(C₆-C₁₀ aryl) and —(C₀-C₃ alkyl)-(C₅-C₁₀heteroaryl), wherein the alkyl, heteroalkyl, cycloalkyl, aryl orheteroaryl group is independently optionally substituted.

In certain embodiments, in (II) R¹ and R³ are independently selectedfrom the group consisting of —(C₆-C₁₀ aryl) and —(C₅-C₁₀ heteroaryl),wherein the aryl or heteroaryl group is independently optionallysubstituted. In other embodiments, in (II) R² is —S(═O)— or —S(═O)₂—. Inyet other embodiments, in (II) R⁴ is —(CH₂)₁₋₃C(═O)NHR⁵. In yet otherembodiments, in (II) R⁵ is selected from the group consisting of —C₁-C₆alkyl, —(C₀-C₃ alkyl)-(C₃-C₈ cycloalkyl), —(C₀-C₃ alkyl)-(C₄-C₁₀heterocyclyl), —(C₀-C₃ alkyl)-(C₆-C₁₀ aryl), and —(C₀-C₃ alkyl)-(C₅-C₁₀heteroaryl), wherein the alkyl, cycloalkyl, heterocyclyl, aryl orheteroaryl group is independently optionally substituted.

In certain embodiments, in (III) each occurrence of R¹ is N. In otherembodiments, in (III) R³ is selected from the group consisting of—S(CH₂)₁₋₃—C(═O)NH₂, —S(CH₂)₁₋₃—C(═O)OR⁵ and —S(CH₂)₁₋₃—C(═O)NHR⁵. Inyet other embodiments, in (III) R⁴ is selected from the group consistingof —(CH₂)₁₋₃—C(═O)OR⁵, —(CH₂)₁₋₃—C(═O)NH₂, and —(CH₂)₁₋₃—C(═O)NHR⁵.

In certain embodiments, in (IV) R¹ is selected from the group consistingof —CH₂—(C₄-C₁₀ heterocyclyl), —CH₂—(C₆-C₁₀ aryl) and —CH₂—(C₅-C₁₀heteroaryl). In other embodiments, in (IV) R² is —(CH₂)₁₋₃—C(═O)NHR⁴. Inyet other embodiments, in (IV) R³ is —S(═O)₂NHR⁴.

In certain embodiments, the compound of the invention is at least oneselected from the group consisting of: cyclohexyl2-((5-((2-((3-chlorophenyl)amino)thiazol-4-yl)methyl)-4-(furan-2-ylmethyl)-4H-1,2,4-triazol-3-yl)thio)acetate;3-(4-(furan-2-ylmethyl)-5-(((2-(phenylamino)thiazol-4-yl)methyl)thio)-4H-1,2,4-triazol-3-yl)propanamide;ethyl2-(((4-(3-chlorophenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)methyl)thiazole-4-carboxylate;2-(((4-(3-chlorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl)thio)methyl)-N-(furan-2-ylmethyl)thiazole-4-carboxamide;N′-(2-((4-butyl-5-((2-((3-chlorophenyl)amino)thiazol-4-yl)methyl)-4H-1,2,4-triazol-3-yl)thio)acetyl)furan-2-carbohydrazide;2-((5-((2-((4-fluorophenyl)amino)thiazol-4-yl)methyl)-4-(furan-2-ylmethyl)-4H-1,2,4-triazol-3-yl)thio)acetamide;2-(((4-(3-chlorophenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)methyl)-N-cyclohexylthiazole-4-carboxamide;2-((4-allyl-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)-N-(benzo[d]thiazol-2-yl)acetamide;N-(4,5-dimethylthiazol-2-yl)-2-((4-ethyl-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)acetamide;2-((5-((2-((4-ethoxyphenyl)amino)thiazol-4-yl)methyl)-4-ethyl-4H-1,2,4-triazol-3-yl)thio)-N-(furan-2-ylmethyl)acetamide;N-(2-(cyclohexylamino)-2-oxoethyl)-2-((2-((4-fluorophenyl)amino)-2-oxoethyl)sulfinyl)-N-(naphthalen-1-yl)acetamide;(N-cyclohexyl-N2-[({2-[(4-fluorophenyl)amino]-2-oxoethyl}sulfinyl)acetyl]-N²-1-naphthylglycinamide);(N²-({[2-(1,3-benzodioxol-5-ylamino)-2-oxoethyl]sulfinyl}acetyl)-N²-(2-chlorobenzyl)-N-cyclopentylglycinamide);N-(2-(tert-butylamino)-2-oxoethyl)-2-((2-((4-fluorophenyl)amino)-2-oxoethyl)sulfinyl)-N-(m-tolyl)acetamide;(2-[5-{[2-(cyclopentylamino)-2-oxoethyl]sulfanyl}-3-(4-pyridinyl)-1H-1,2,4-triazol-1-yl]-N-(3-methoxyphenyl)acetamide);N²-(1,3-benzodioxol-5-ylmethyl)-N²-{[4-(cyclopentylsulfamoyl)phenyl]sulfonyl}-N-phenylglycinamide;2-amino-4-(2,7-diethoxynaphthalen-1-yl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile;ethyl2-methyl-4-(naphthalen-1-yl)-5-oxo-7-phenyl-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate;methyl7-(3,4-dimethoxyphenyl)-2-methyl-4-(naphthalen-1-yl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate;2-methoxyethyl2-methyl-4-(naphthalen-1-yl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate;methyl7-(4-methoxyphenyl)-2-methyl-4-(naphthalen-1-yl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate;ethyl4-(anthracen-9-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate(KA820);3-(furan-2-ylmethyl)-8-(naphthalen-1-yl)-6-oxo-3,4,7,8-tetrahydro-2H,6H-pyrido[2,1-b][1,3,5]thiadiazine-9-carbonitrile;6-amino-4-(2-hydroxynaphthalen-1-yl)-3-methyl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile;2-((3-cyano-4-(naphthalen-1-yl)-6-oxo-1,4,5,6-tetrahydropyridin-2-yl)thio)-N-phenylacetamide;methyl6-amino-5-cyano-2-(methoxymethyl)-4-(naphthalen-1-yl)-4H-pyran-3-carboxylate;2-amino-4-(naphthalen-1-yl)-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-carbonitrile;1,3-dimethyl-5-(naphthalen-1-yl)-5,11-dihydro-1H-indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine-2,4,6(3H)-trione;2-amino-5-(naphthalen-1-yl)-5,11-dihydro-1H-indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine-4,6-dione;3-(4-chlorophenyl)-7-(4-fluorophenyl)-3H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-c]pyrimidine;3-(2-chlorobenzyl)-7-(4-fluorophenyl)-5-methyl-3H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-c]pyrimidine;7-(4-(1H-tetrazol-1-yl)phenyl)-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-c]pyrimidine;4-(5-(4-butoxyphenyl)-4-phenyl-4H-1,2,4-triazol-3-yl)-2-(p-tolyl)quinolone;4-(5-(4-(tert-butyl)phenyl)-4-(p-tolyl)-4H-1,2,4-triazol-3-yl)pyridine;3-(5-(4-butoxyphenyl)-4-phenyl-4H-1,2,4-triazol-3-yl)aniline; or a salt,tautomer or solvate thereof.

In certain embodiments, the pharmaceutical composition further comprisesa pharmaceutically acceptable carrier. In other embodiments, thecompound is formulated as a pharmaceutical composition. In otherembodiments, the pharmaceutical composition further comprises at leastone additional therapeutic agent selected from the group consisting ofanakinra, rilonacept, azathioprine, methotrexate, bosentan, etanercept,halofuginone, iloprost, cyclophosphamide, cyclosporin A, mycophenolatemofetil, intravenous immunoglobulin, pirfenidone, prednisone, rituximab,beta-glycan peptides, basiliximab, sirolimus, alefacept, terguride,pomalidomide, and a tyrosine kinase inhibitor.

In certain embodiments, the disease or disorder is an infectious,inflammatory or autoimmune disease or disorder. In other embodiments,the disease or disorder is selected from the group consisting ofscleroderma, inflammation in general, systemic lupus erythematosus(lupus), Sjogren's syndrome, arthritis, myositis, Behcet's disease,inflammatory bowel disease, colitis, septic shock, chronic myelogenousleukemia, acute myelogenous leukemia, multiple myeloma, non-bloodcancers, psoriasis, type I and type II diabetes, asbestosis, idiopathicpulmonary fibrosis, graft-versus-host disease, familial Mediterraneanfever, stroke, epilepsy, and cryopyrin-associated periodic syndromes(CAPS). In yet other embodiments, the non-blood cancer comprises atleast one selected from the group consisting of glioma, metastaticbreast cancer, interleukin-1-producing cancer, pancreatic ductaladenocarcinoma, colorectal, melanoma, gastric carcinoma, cervicalcancer, lung carcinoma, and ovarian carcinoma.

In certain embodiments, the mammal is further administered at least oneadditional therapeutic agent. In other embodiments, the additionaltherapeutic agent comprises at least one selected from the groupconsisting of anakinra, rilonacept, azathioprine, methotrexate,bosentan, etanercept, halofuginone, iloprost, cyclophosphamide,cyclosporin A, mycophenolate mofetil, intravenous immunoglobulin,pirfenidone, prednisone, rituximab, beta-glycan peptides, basiliximab,sirolimus, alefacept, terguride, pomalidomide, and a tyrosine kinaseinhibitor. In yet other embodiments, the mammal and the additionaltherapeutic agent are co-administered to the mammal. In yet otherembodiments, the compound is administered to the mammal a given periodof time before or after the additional therapeutic agent is administeredto the mammal. In yet other embodiments, the mammal is human.

BRIEF DESCRIPTION OF THE DRAWINGS

The following detailed description of specific embodiments of theinvention will be better understood when read in conjunction with theappended drawings. For the purpose of illustrating the invention, thereare shown in the drawings specific embodiments. It should be understood,however, that the invention is not limited to the precise arrangementsand instrumentalities of the embodiments shown in the drawings.

FIG. 1 is a non-limiting schematic representation of the in silicomodeling of a compound of the invention bound to IL-1R. IL-1R isrepresented as ribbons and

FIG. 2 is a non-limiting schematic representation of KA862 bound toIL-1R.

FIG. 3 is a non-limiting illustration of representative compounds of theinvention.

FIG. 4 is a non-limiting illustration of representative compounds of theinvention.

FIG. 5 is a set of graphs illustrating target validation studies.Selected small molecules downregulated collagen synthesis in SScfibroblasts. SSc dermal fibroblasts were treated for 48 h with 100 μM or10 μM of compound, then media was collected and total collagen wasmeasured by hydroxyproline. Samples were tested in triplicate acrossdifferent patient samples and expressed as the mean±SEM (n=4).*p<0.0001, **p=0.02.

FIG. 6 is a graph illustrating target validation studies that assessedthe direct blocking of IL-1 signaling in fibroblasts in normalfibroblasts.

FIG. 7 is a set of bar graphs illustrating the finding that compounds ofthe invention are effective against bleomycin induced fibrosis in an invitro model. Top graph: normal fibroblasts stimulated with bleomycin(Bleo)+IL-1RA (n=3); bottom graph: normal fibroblasts stimulated withBleo+KA862 (n=3).

FIG. 8 is a set of images and bar graph illustrating the inhibition bycompounds of the invention of secretion of COL1A1 into culture media bySSc fibroblasts.

FIG. 9 is a set of graphs illustrating the IC₅₀ determination for KA521,KA222, KA306, and KA695. Decreasing concentrations of compound weretested against 10 μM bleomycin for 48 h and hydroxyproline measured inthe culture media. IC₅₀ was found to be approximately 1 nM for KA222,KA306 and KA695 in this assay.

FIG. 10 is a graph illustrating the finding that exemplary compounds ofthe invention inhibit collagen production by SSc fibroblasts. SScfibroblasts were treated for 48 h with 1 nM compound, and then culturemedia was recovered and hydroxyproline was measured. Samples were testedin triplicate across different patient samples and expressed as themean±SEM (n=3 independent patient samples).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the unexpected discovery of smallmolecule compounds that are useful to treat or ameliorate anIL-1R-mediated disease or disorder in a mammal. In certain embodiments,the disease or disorder includes scleroderma. In other embodiments, thecompounds of the invention inhibit or modulate IL-1R signaling. In otherembodiments, the compounds of the invention block or modulate thesynthesis of collagen in the mammal and thus block or modulate fibrosisin the mammal. In yet other embodiments, the compounds of the inventionare useful in combination with other therapeutic agents, such as but notlimited to anakinra and/or rilonacept.

In one aspect, the compounds of the invention are useful in treating anyIL-1R-mediated diseases or disorders. In certain embodiments, thecompounds of the invention are useful in treating or preventinginfectious, inflammatory and/or autoimmune diseases or disorders, notlimited to scleroderma, and inflammation in general, such as systemiclupus erythematosus (lupus), Sjogren's syndrome, arthritis [includingrheumatoid arthritis, juvenile rheumatoid arthritis (also known asjuvenile idiopathic arthritis or Still's disease), adult onset Still'sdisease, psoriatic arthritis, osteoarthritis, and spondylarthritis],myositis [including polymyositis, dermatomyositis, inclusion bodymyositis], Behcet's disease, inflammatory bowel disease, colitis, septicshock, chronic myelogenous leukemia, acute myelogenous leukemia,multiple myeloma, non-blood cancers (such as, but not limited to,glioma, metastatic breast cancer, cancers producing interleukin-1,pancreatic ductal adenocarcinoma, colorectal, melanoma, gastriccarcinoma, cervical cancer, lung carcinoma, and ovarian carcinoma),psoriasis, type I and type II diabetes, asbestosis, idiopathic pulmonaryfibrosis, graft-versus-host disease, familial Mediterranean fever,stroke, epilepsy, and cryopyrin-associated periodic syndromes (CAPS,including familial cold autoinflammatory syndrome, Muckle-Wells syndromeand neonatal onset multisystem inflammatory disease).

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, the preferred methodsand materials are described.

As used herein, each of the following terms has the meaning associatedwith it in this section.

The articles “a” and “an” are used herein to refer to one or to morethan one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The term “about” as used herein, when referring to a measurable valuesuch as an amount, a temporal duration, and the like, is meant toencompass variations of ±20% or ±10%, more preferably ±5%, even morepreferably ±1%, and still more preferably ±0.1% from the specifiedvalue, as such variations are appropriate to perform the disclosedmethods.

As used herein, the term “alkoxy” employed alone or in combination withother terms means, unless otherwise stated, an alkyl group having thedesignated number of carbon atoms, as defined above, connected to therest of the molecule via an oxygen atom, such as, for example, methoxy,ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and the higher homologs andisomers. Preferred are C₁-C₃ alkoxy, particularly ethoxy and methoxy.

As used herein, the term “alkyl” by itself or as part of anothersubstituent means, unless otherwise stated, a straight or branched chainhydrocarbon having the number of carbon atoms designated (i.e., C₁₋₆means one to six carbon atoms) and includes straight, branched chain, orcyclic substituent groups. Examples include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, andcyclopropylmethyl. Examples include C₁-C₆ alkyl, particularly ethyl,methyl, isopropyl, isobutyl, n-pentyl, n-hexyl and cyclopropylmethyl. C₀alkyl corresponds to a bond.

As used herein, the term “substituted alkyl” means alkyl, as definedabove, substituted by one, two or three substituents selected from thegroup consisting of halogen, —OH, alkoxy, —NH₂, —N(CH₃)₂, —C(═O)OH,trifluoromethyl, —C≡N, —C(═O)O(C₁-C₄)alkyl, —C(═O)NH₂, —SO₂NH₂,—C(═NH)NH₂, and —NO₂, preferably containing one or two substituentsselected from halogen, —OH, alkoxy, —NH₂, trifluoromethyl, —N(CH₃)₂, and—C(═O)OH, more preferably selected from halogen, alkoxy and —OH.Examples of substituted alkyls include, but are not limited to,2,2-difluoropropyl, 2-carboxy cyclopentyl and 3-chloropropyl.

As used herein, the term “aromatic” refers to a carbocycle orheterocycle with one or more polyunsaturated rings and having aromaticcharacter, i.e., having (4n+2) delocalized π (pi) electrons, where n isan integer.

As used herein, the term “aryl,” employed alone or in combination withother terms, means, unless otherwise stated, a carbocyclic aromaticsystem containing one or more rings (typically one, two or three rings)wherein such rings may be attached together in a pendent manner, such asa biphenyl, or may be fused, such as naphthalene. Examples includephenyl, anthracyl, and naphthyl. Preferred are phenyl and naphthyl, mostpreferred is phenyl.

As used herein, the term “aryl-(C₁-C₃ alkyl)” means a functional groupwherein a one to three carbon alkylene chain is attached to an arylgroup, e.g., —CH₂CH₂-phenyl. Preferred is aryl-CH₂— and aryl-CH(CH₃)—.The term “substituted aryl-(C₁-C₃ alkyl)” means an aryl-(C₁-C₃ alkyl)functional group in which the aryl group is substituted. Preferred issubstituted aryl(CH₂)—. Similarly, the term “heteroaryl-(C₁-C₃ alkyl)”means a functional group wherein a one to three carbon alkylene chain isattached to a heteroaryl group, e.g., —CH₂CH₂-pyridyl. Preferred isheteroaryl-(CH₂)—. The term “substituted heteroaryl-(C₁-C₃)alkyl” meansa heteroaryl-(C₁-C₃ alkyl) functional group in which the heteroarylgroup is substituted. Preferred is substituted heteroaryl-(CH₂)—.

The term “container” includes any receptacle for holding thepharmaceutical composition. For example, in certain embodiments, thecontainer is the packaging that contains the pharmaceutical composition.In other embodiments, the container is not the packaging that containsthe pharmaceutical composition, i.e., the container is a receptacle,such as a box or vial that contains the packaged pharmaceuticalcomposition or unpackaged pharmaceutical composition and theinstructions for use of the pharmaceutical composition. Moreover,packaging techniques are well known in the art. It should be understoodthat the instructions for use of the pharmaceutical composition may becontained on the packaging containing the pharmaceutical composition,and as such the instructions form an increased functional relationshipto the packaged product. However, it should be understood that theinstructions may contain information pertaining to the compound'sability to perform its intended function, e.g., treating, preventing, orreducing an IL-1R-mediated disease or disorder in a patient.

As used herein, the terms “effective amount” and “pharmaceuticallyeffective amount” and “therapeutically effective amount” refer to anontoxic but sufficient amount of an agent or compound to provide thedesired biological result. That result may be reduction and/oralleviation of the signs, symptoms, or causes of a disease, or any otherdesired alteration of a biological system. An appropriate therapeuticamount in any individual case may be determined by one of ordinary skillin the art using routine experimentation.

As used herein, the term “halo” or “halogen” alone or as part of anothersubstituent means, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom, preferably, fluorine, chlorine, or bromine,more preferably, fluorine or chlorine.

As used herein, the term “heteroalkyl” by itself or in combination withanother term means, unless otherwise stated, a stable straight orbranched chain alkyl group consisting of the stated number of carbonatoms and one or two heteroatoms selected from the group consisting ofO, N, and S, and wherein the nitrogen and sulfur atoms may be optionallyoxidized and the nitrogen heteroatom may be optionally quaternized. Theheteroatom(s) may be placed at any position of the heteroalkyl group,including between the rest of the heteroalkyl group and the fragment towhich it is attached, as well as attached to the most distal carbon atomin the heteroalkyl group. Examples include: —O—CH₂—CH₂—CH₃,—CH₂—CH₂—CH₂—OH, —CH₂—CH₂—NH—CH₃, —CH₂—S—CH₂—CH₃, and —CH₂CH₂—S(═O)—CH₃.Up to two heteroatoms may be consecutive, such as, for example,—CH₂—NH—OCH₃, or —CH₂—CH₂—S—S—CH₃

As used herein, the term “heterocycle” or “heterocyclyl” or“heterocyclic” by itself or as part of another substituent means, unlessotherwise stated, an unsubstituted or substituted, stable, mono- ormulti-cyclic heterocyclic ring system that consists of carbon atoms andat least one heteroatom selected from the group consisting of N, O, andS, and wherein the nitrogen and sulfur heteroatoms may be optionallyoxidized, and the nitrogen atom may be optionally quaternized. Theheterocyclic system may be attached, unless otherwise stated, at anyheteroatom or carbon atom that affords a stable structure. A heterocyclemay be aromatic or non-aromatic in nature. In certain embodiments, theheterocycle is a heteroaryl.

As used herein, the term “heteroaryl” or “heteroaromatic” refers to aheterocycle having aromatic character. A polycyclic heteroaryl mayinclude one or more rings that are partially saturated. Examples includetetrahydroquinoline and 2,3-dihydrobenzofuryl.

Examples of non-aromatic heterocycles include monocyclic groups such asaziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine,pyrroline, imidazoline, pyrazolidine, dioxolane, sulfolane,2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane,piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine,morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran,1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine, 1,3-dioxepane,4,7-dihydro-1,3-dioxepin and hexamethyleneoxide.

Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl(particularly 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl,pyrrolyl (particularly 2-pyrrolyl), imidazolyl, thiazolyl, oxazolyl,pyrazolyl (particularly 3- and 5-pyrazolyl), isothiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl,1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and1,3,4-oxadiazolyl.

Examples of polycyclic heterocycles include indolyl (particularly 3-,4-, 5-, 6- and 7-indolyl), indolinyl, quinolyl, tetrahydroquinolyl,isoquinolyl (particularly 1- and 5-isoquinolyl),1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl (particularly 2-and 5-quinoxalinyl), quinazolinyl, phthalazinyl, 1,8-naphthyridinyl,1,4-benzodioxanyl, coumarin, dihydrocoumarin, 1,5-naphthyridinyl,benzofuryl (particularly 3-, 4-, 5-, 6- and 7-benzofuryl),2,3-dihydrobenzofuryl, 1,2-benzisoxazolyl, benzothienyl (particularly3-, 4-, 5-, 6-, and 7-benzothienyl), benzoxazolyl, benzothiazolyl(particularly 2-benzothiazolyl and 5-benzothiazolyl), purinyl,benzimidazolyl (particularly 2-benzimidazolyl), benztriazolyl,thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrrolizidinyl, andquinolizidinyl.

The aforementioned listing of heterocyclyl and heteroaryl moieties isintended to be representative and not limiting.

As used herein, the term “IL-1R-mediated disease or disorder” refers toany disease or disorder that is triggered, caused, potentiated,exacerbated, intensified, complicated and/or compounded by the normal orabnormally increased concentration, expression level and/or activity ofIL-1R in a mammal. The normal or abnormally increased concentration,expression level and/or activity of IL-1R in a mammal may be determinedby examining a mammal who is healthy and/not affected by such disease ordisorder. Non-limiting examples of IL-1R-mediated diseases or disordersare infectious, inflammatory and/or autoimmune diseases or disorders,not limited to scleroderma, inflammation in general, systemic lupuserythematosus (lupus), Sjogren's syndrome, arthritis [includingrheumatoid arthritis, juvenile rheumatoid arthritis (also known asjuvenile idiopathic arthritis or Still's disease), adult onset Still'sdisease, psoriatic arthritis, osteoarthritis, and spondylarthritis],myositis [including polymyositis, dermatomyositis, inclusion bodymyositis], Behcet's disease, inflammatory bowel disease, colitis, septicshock, chronic myelogenous leukemia, acute myelogenous leukemia,multiple myeloma, non-blood cancers (such as, but not limited to,glioma, metastatic breast cancer, cancers producing interleukin-1,pancreatic ductal adenocarcinoma, colorectal, melanoma, gastriccarcinoma, cervical cancer, lung carcinoma, and ovarian carcinoma),psoriasis, type I and type II diabetes, asbestosis, idiopathic pulmonaryfibrosis, graft-versus-host disease, familial Mediterranean fever,stroke, epilepsy, and cryopyrin-associated periodic syndromes (CAPS,including familial cold autoinflammatory syndrome, Muckle-Wells syndromeand neonatal onset multisystem inflammatory disease).

As used herein, the term “KA199” refers to the compound(N²-(1,3-Benzodioxol-5-ylmethyl)-N²-{[4-(cyclopentylsulfamoyl)phenyl]sulfonyl}-N-phenylglycinamide),or a salt, tautomer or solvate thereof.

As used herein, the term “KA222” refers to the compound6-amino-4-(2-hydroxynaphthalen-1-yl)-3-methyl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile,or a salt, tautomer or solvate thereof.

As used herein, the term “KA306” refers to the compound methyl7-(3,4-dimethoxyphenyl)-2-methyl-4-(naphthalen-1-yl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate,or a salt, tautomer or solvate thereof.

As used herein, the term “KA494” refers to the compoundN-(2-(cyclohexylamino)-2-oxoethyl)-2-((2-((4-fluorophenyl)amino)-2-oxoethyl)sulfinyl)-N-(naphthalen-1-yl)acetamide,or a salt, tautomer or solvate thereof.

As used herein, the term “KA521” refers to the compound7-(4-(1H-tetrazol-1-yl)phenyl)-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-c]pyrimidine,or a salt, tautomer or solvate thereof.

As used herein, the term “KA529” refers to the compound2-[5-{[2-(cyclopentylamino)-2-oxoethyl]sulfanyl}-3-(4-pyridinyl)-1H-1,2,4-triazol-1-yl]-N-(3-methoxyphenyl)acetamide,or a salt, tautomer or solvate thereof.

As used herein, the term “KA680” refers toN²-({[2-(1,3-benzodioxol-5-ylamino)-2-oxoethyl]sulfinyl}acetyl)-N²-(2-chlorobenzyl)-N-cyclopentylglycinamide,or a salt, tautomer or solvate thereof.

As used herein, the term “KA695” refers to the compound 2-methoxyethyl2-methyl-4-(naphthalen-1-yl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate,or a salt, tautomer or solvate thereof.

As used herein, the term “KA862” refers to the compound cyclohexyl2-((5-((2-((3-chlorophenyl)amino)thiazol-4-yl)methyl)-4-(furan-2-ylmethyl)-4H-1,2,4-triazol-3-yl)thio)acetate,or a salt, tautomer or solvate thereof.

As used herein, the terms “patient” and “subject” and “individual” referinterchangeably to a human or a non-human mammal. Non-human mammalsinclude, for example, livestock and pets, such as ovine, bovine,porcine, canine, feline and murine mammals. Preferably, the patient orsubject is human.

As used herein, the term “pharmaceutical composition” refers to amixture of at least one compound useful in the methods of the inventionwith a pharmaceutically acceptable carrier. The pharmaceuticalcomposition facilitates administration of the compound to a patient.Multiple techniques of administering a compound exist in the artincluding, but not limited to, intravenous, oral, aerosol, parenteral,ophthalmic, pulmonary and topical administration.

As used herein, the term “pharmaceutically acceptable” refers to amaterial, such as a carrier or diluent, which does not abrogate thebiological activity or properties of the compound, and is relativelynon-toxic, i.e., the material may be administered to an individualwithout causing undesirable biological effects or interacting in adeleterious manner with any of the components of the composition inwhich it is contained.

As used herein, the term “pharmaceutically acceptable carrier” means apharmaceutically acceptable material, composition or carrier, such as aliquid or solid filler, stabilizer, dispersing agent, suspending agent,diluent, excipient, thickening agent, solvent or encapsulating material,involved in carrying or transporting a compound useful in the methods ofthe invention within or to the patient such that it may perform itsintended function. Typically, such constructs are carried or transportedfrom one organ, or portion of the body, to another organ, or portion ofthe body. Each carrier must be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation, including thecompound useful in the methods of the invention, and not injurious tothe patient. Some examples of materials that may serve aspharmaceutically acceptable carriers include: sugars, such as lactose,glucose and sucrose; starches, such as corn starch and potato starch;cellulose, and its derivatives, such as sodium carboxymethyl cellulose,ethyl cellulose and cellulose acetate; powdered tragacanth; malt;gelatin; talc; excipients, such as cocoa butter and suppository waxes;oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil,olive oil, corn oil and soybean oil; glycols, such as propylene glycol;polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol;esters, such as ethyl oleate and ethyl laurate; agar; buffering agents,such as magnesium hydroxide and aluminum hydroxide; surface activeagents; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol; phosphate buffer solutions; and other non-toxiccompatible substances employed in pharmaceutical formulations.

As used herein, “pharmaceutically acceptable carrier” also includes anyand all coatings, antibacterial and antifungal agents, and absorptiondelaying agents, and the like that are compatible with the activity ofthe compound useful in the methods of the invention, and arephysiologically acceptable to the patient. Supplementary activecompounds may also be incorporated into the compositions. The“pharmaceutically acceptable carrier” may further include apharmaceutically acceptable salt of the compound useful in the methodsof the invention. Other additional ingredients that may be included inthe pharmaceutical compositions used in the practice of the inventionare known in the art and described, for example in Remington'sPharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton,Pa.), which is incorporated herein by reference.

As used herein, the term “prevent” or “prevention” means no disorder ordisease development if none had occurred, or no further disorder ordisease development if there had already been development of thedisorder or disease. Also considered is the ability of one to preventsome or all of the symptoms associated with the disorder or disease.

As used herein, the term “salts” embraces addition salts of free acidsor bases that are useful within the methods of the invention. In certainembodiments, the salts are pharmaceutically acceptable salts. Thelanguage “pharmaceutically acceptable salt” refers to a salt of theadministered compounds prepared from pharmaceutically acceptablenon-toxic acids or bases, including inorganic acids or bases, organicacids or bases, and solvates, hydrates, or clathrates thereof.Pharmaceutically unacceptable salts may nonetheless possess propertiessuch as high crystallinity, which have utility in the practice of thepresent invention, such as for example utility in process of synthesis,purification or formulation of compounds useful within the methods ofthe invention.

Suitable pharmaceutically acceptable acid addition salts may be preparedfrom an inorganic acid or from an organic acid. Examples of inorganicacids include sulfate, hydrogen sulfate, hydrochloric, hydrobromic,hydriodic, nitric, carbonic, sulfuric, and phosphoric acids (includinghydrogen phosphate and dihydrogen phosphate). Appropriate organic acidsmay be selected from aliphatic, cycloaliphatic, aromatic, araliphatic,heterocyclic, carboxylic and sulfonic classes of organic acids, examplesof which include formic, acetic, propionic, succinic, glycolic,gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic,fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic,ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic,2-hydroxyethanesulfonic, p-toluene sulfonic, sulfanilic,cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric, salicylic,galactaric and galacturonic acid.

Suitable pharmaceutically acceptable base addition salts of compounds ofthe invention include, for example, ammonium salts, metallic saltsincluding alkali metal, alkaline earth metal and transition metal saltssuch as, for example, calcium, magnesium, potassium, sodium and zincsalts. Pharmaceutically acceptable base addition salts also includeorganic salts made from basic amines such as, for example,N,N′-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine. All ofthese salts may be prepared from the corresponding compound by reacting,for example, the appropriate acid or base with the compound.

As used herein, the term “substituted” means that an atom or group ofatoms has replaced hydrogen as the substituent attached to anothergroup.

For aryl, aryl-(C₁-C₃ alkyl) and heterocyclyl groups, the term“substituted” as applied to the rings of these groups refers to anylevel of substitution, namely mono-, di-, tri-, tetra-, orpenta-substitution, where such substitution is permitted. Thesubstituents are independently selected, and substitution may be at anychemically accessible position. In certain embodiments, the substituentsvary in number between one and four. In other embodiments, thesubstituents vary in number between one and three. In yet otherembodiments, the substituents vary in number between one and two. In yetother embodiments, the substituents are independently selected from thegroup consisting of C₁-C₆ alkyl, —OH, C₁-C₆ alkoxy, halo, amino,acetamido and nitro. In yet other embodiments, the substituents areindependently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆alkoxy, halo, acetamido, and nitro. As used herein, where a substituentis an alkyl or alkoxy group, the carbon chain may be branched, straightor cyclic, with straight being preferred.

As used herein, the term “treatment” or “treating,” is defined as theapplication or administration of a therapeutic compound, i.e., acompound of the invention (alone or in combination with anothertherapeutic agent), to a patient, or application or administration of atherapeutic compound to an isolated tissue or cell line from a patient(e.g., for diagnosis or ex vivo applications), who has an IL-1R-mediateddisease or disorder, a symptom of an IL-1R-mediated disease or disorder,or the potential to develop an IL-1R-mediated disease or disorder, withthe purpose to cure, heal, alleviate, relieve, alter, remedy,ameliorate, improve or affect an IL-1R-mediated disease or disorder, thesymptoms of an IL-1R-mediated disease or disorder or the potential todevelop an IL-1R-mediated disease or disorder. Such treatments may bespecifically tailored or modified, based on knowledge obtained from thefield of pharmacogenomics.

Ranges: throughout this disclosure, various aspects of the invention canbe presented in a range format. It should be understood that thedescription in range format is merely for convenience and brevity andshould not be construed as an inflexible limitation on the scope of theinvention. Accordingly, the description of a range should be consideredto have specifically disclosed all the possible subranges as well asindividual numerical values within that range. For example, descriptionof a range such as from 1 to 6 should be considered to have specificallydisclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numberswithin that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. Thisapplies regardless of the breadth of the range.

Description

The present invention relates to the unexpected discovery of smallmolecule compounds that are useful to treat or ameliorate anIL-1R-mediated disease or disorder in a mammal. In certain embodiments,the disease or disorder includes scleroderma. In other embodiments, thecompounds of the invention inhibit or modulate IL-1R signaling. In otherembodiments, the compounds of the invention block or modulate thesynthesis of collagen in the mammal and thus block or modulate fibrosisin the mammal. In yet other embodiments, the compounds of the inventionare useful in combination with other therapeutic agents, such as but notlimited to anakinra and/or rilonacept. In yet other embodiments, thecompounds of the invention are useful in treating or preventinginfectious, inflammatory and/or autoimmune diseases or disorders.

As demonstrated therein, in certain embodiments, the compounds of theinvention were designed using the novel in silico screening technologycalled the Hybrid Structure Based (HSB) method. As a working hypothesis,inhibition of IL-1R leads to downstream modulation of collagen synthesisand thus controls fibrosis. In certain embodiments, the compounds of theinvention block the interaction of IL-1α with 1L-1R. In otherembodiments, the compounds of the invention block the interaction ofIL-1β with 1L-1R. In yet other embodiments, the compounds of theinvention block the interaction of IL-1α and IL-1β with 1L-1R.

As demonstrated herein, KA199, KA494, KA529, KA680, and KA862 were alleffective at reducing total collagen secretion into the culture media asmeasured by hydroxyproline (FIG. 5). Western blotting for specific ECMproteins demonstrate that these compounds lower collagen secreted intoculture media (FIGS. 7-8).

As demonstrated herein, KA494 and KA862 were found to be efficacious inblocking collagen synthesis when tested in vitro using fibroblastsderived from scleroderma patients and normal fibroblasts stimulated with10 μM bleomycin to replicate scleroderma fibroblasts. Without wishing tobe limited by any theory, designing a focused screening library allowsfor the identification of analogs with favorable drug-like propertiesand binding efficacy against IL-1R. Compounds of interest may be testedin vitro using patient-derived scleroderma fibroblasts, normalfibroblasts treated with bleomycin to increase collagen synthesis, andin vivo in scleroderma animal models.

Compounds and Compositions

The compounds useful in the methods of the invention may be synthesizedusing techniques well-known in the art of organic synthesis.

In one aspect, the compound is the compound of formula (I), or salt,tautomer or solvate thereof:

wherein in (I), ring A is selected from the group consisting of:

wherein in ring A one occurrence of R¹ is CR⁶ and the other occurrenceof R¹ is N or CR⁷ and the furan rings are independently optionallysubstituted with R⁷; R² is selected from the group consisting of bond,—CH₂S—, —SCH₂—, —CH₂O—, —OCH₂—, —(CH₂)₁₋₆—, arylene, heteroarylene, andcombinations thereof; R³ is selected from the group consisting of —C₁-C₆alkyl, —C₂-C₆ alkenyl, —C₁-C₆ heteroalkyl, —(C₀-C₃ alkyl)-(C₃-C₈cycloalkyl), —(C₀-C₃ alkyl)-(C₄-C₁₀ heterocyclyl), —(C₀-C₃alkyl)-(C₆-C₁₀ aryl) and —(C₀-C₃ alkyl)-(C₅-C₁₀ heteroaryl), wherein thealkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl orheteroaryl group is independently optionally substituted; R⁴ is selectedfrom the group consisting of —C₁-C₆ alkyl, —C₁-C₆ heteroalkyl, —(C₀-C₃alkyl)-(C₃-C₈ cycloalkyl), —(C₀-C₃ alkyl)-(C₄-C₁₀ heterocyclyl), —(C₀-C₃alkyl)-(C₆-C₁₀ aryl), —(C₀-C₃ alkyl)-(C₅-C₁₀ heteroaryl),—(CH₂)₁₋₃—C(═O)NH₂, —(CH₂)₁₋₃—C(═O)NHNHC(═O)R⁵, —S(CH₂)₁₋₃—C(═O)NH₂,—S(CH₂)₁₋₃—C(═O)NHR⁸, —S(CH₂)₁₋₃—C(═O)OR³ and—S(CH₂)₁₋₃—C(═O)NHNHC(═O)R⁵, wherein the alkyl, heteroalkyl, cycloalkyl,heterocyclyl, aryl or heteroaryl group is independently optionallysubstituted; each occurrence of R⁵ is independently —C₄-C₁₀heterocyclyl, —C₆-C₁₀ aryl or —C₅-C₁₀ heteroaryl, wherein theheterocyclyl, aryl or heteroaryl group is independently optionallysubstituted; each occurrence of R⁶ is independently selected from thegroup consisting of —NHR⁸, —C(═O)OH, —C(═O)OR⁸ and —C(═O)NHR⁸; eachoccurrence of R⁷ is independently H, halo, —C₁-C₆ alkyl or —C₃-C₁₀cycloalkyl, wherein the alkyl or cycloalkyl group is independentlyoptionally substituted; and each occurrence of R⁸ is independentlyselected from the group consisting of —C₁-C₆ alkyl, —C₁-C₆ heteroalkyl,—(C₀-C₃ alkyl)-(C₃-C₈ cycloalkyl), —(C₀-C₃ alkyl)-(C₄-C₁₀ heterocyclyl),—(C₀-C₃ alkyl)-(C₆-C₁₀ aryl) and —(C₀-C₃ alkyl)-(C₅-C₁₀ heteroaryl),wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl orheteroaryl group is independently optionally substituted.

In certain embodiments, ring A is selected from the group consisting of:

In other embodiments, ring A is selected from the group consisting of:

In certain embodiments, in ring A one occurrence of R¹ is CR⁶ and theother occurrence of R¹ is CR⁷.

In certain embodiments, R² is selected from the group consisting of—CH₂S—, —SCH₂— and —(CH₂)₁₋₆—.

In certain embodiments, R³ is selected from the group consisting of—C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₃-C₈ cycloalkyl, —(C₀-C₃ alkyl)-(C₆-C₁₀aryl) and —(C₀-C₃ alkyl)-(C₅-C₁₀ heteroaryl), wherein the alkyl,alkenyl, cycloalkyl, aryl or heteroaryl group is independentlyoptionally substituted. In other embodiments, R³ is selected from thegroup consisting of —C₁-C₆ alkyl, —C₂-C₆ alkenyl, furan-2-ylmethyl andfuran-3-ylmethyl.

In certain embodiments, R⁴ is selected from the group consisting ofC₁-C₆ alkyl, —(C₀-C₃ alkyl)-(C₆-C₁₀ aryl), —(C₀-C₃ alkyl)-(C₅-C₁₀heteroaryl), —(CH₂)₁₋₃—C(═O)NH₂, —S(CH₂)₁₋₃—C(═O)NH₂,—S(CH₂)₁₋₃—C(═O)OR³ and —S(CH₂)₁₋₃—C(═O)NHNHC(═O)R⁵.

In certain embodiments, R⁵ is C₆-C₁₀ aryl or C₅-C₁₀ heteroaryl, whereinthe aryl or heteroaryl group is independently optionally substituted.

In certain embodiments, R⁶ is selected from the group consisting of—NHR⁸ and —C(═O)NHR⁸.

In certain embodiments, R⁷ is H, halo or C₁-C₆ alkyl, wherein the alkylgroup is optionally substituted. In other embodiments, R⁷ is H or halo.

In certain embodiments, R⁸ is selected from the group consisting of—(C₀-C₃ alkyl)-(C₃-C₈ cycloalkyl), —(C₀-C₃ alkyl)-(C₆-C₁₀ aryl) and—(C₀-C₃ alkyl)-(C₅-C₁₀ heteroaryl), wherein the alkyl, heteroalkyl,cycloalkyl, aryl or heteroaryl group is independently optionallysubstituted.

In certain embodiments, the compound of the invention is selected fromthe group consisting of:

cyclohexyl2-((5-((2-((3-chlorophenyl)amino)thiazol-4-yl)methyl)-4-(furan-2-ylmethyl)-4H-1,2,4-triazol-3-yl)thio)acetate (KA862):

3-(4-(furan-2-ylmethyl)-5-(((2-(phenylamino)thiazol-4-yl)methyl)thio)-4H-1,2,4-triazol-3-yl)propanamide(1, FIG. 3):

ethyl2-(((4-(3-chlorophenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)methyl)thiazole-4-carboxylate (2, FIG. 3):

2-(((4-(3-chlorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl)thio)methyl)-N-(furan-2-ylmethyl)thiazole-4-carboxamide (3, FIG. 3):

N′-(2-((4-butyl-5-((2-((3-chlorophenyl)amino)thiazol-4-yl)methyl)-4H-1,2,4-triazol-3-yl)thio)acetyl)furan-2-carbohydrazide(4, FIG. 3):

2-((5-((2-((4-fluorophenyl)amino)thiazol-4-yl)methyl)-4-(furan-2-ylmethyl)-4H-1,2,4-triazol-3-yl)thio)acetamide(5, FIG. 3):

2-(((4-(3-chlorophenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)methyl)-N-cyclohexylthiazole-4-carboxamide(6, FIG. 3):

2-((4-allyl-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)-N-(benzo[d]thiazol-2-yl)acetamide (KA426):

N-(4,5-dimethylthiazol-2-yl)-2-((4-ethyl-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)acetamide (KA420):

2-((5-((2-((4-ethoxyphenyl)amino)thiazol-4-yl)methyl)-4-ethyl-4H-1,2,4-triazol-3-yl)thio)-N-(furan-2-ylmethyl)acetamide(KA309):

a salt, tautomer or solvate thereof, and any mixtures thereof.

In one aspect, the compound is the compound of formula (II), or salt,tautomer or solvate thereof:

wherein in (II): R¹ and R³ are independently selected from the groupconsisting of —(C₀-C₃ alkyl)-(C₆-C₁₀ aryl), and —(C₀-C₃ alkyl)-(C₅-C₁₀heteroaryl), wherein the alkyl, aryl or heteroaryl group isindependently optionally substituted; R² is S, S(═O) or S(═O)₂; R⁴ isselected from the group consisting of —(CH₂)₁₋₃C(═O)OH,—(CH₂)₁₋₃C(═O)OR⁵ and —(CH₂)₁₋₃C(═O)NHR⁵; and each occurrence of R⁵ isindependently selected from the group consisting of —C₁-C₆ alkyl, —C₁-C₆heteroalkyl, —(C₀-C₃ alkyl)-(C₃-C₈ cycloalkyl), —(C₀-C₃ alkyl)-(C₄-C₁₀heterocyclyl), —(C₀-C₃ alkyl)-(C₆-C₁₀ aryl) and —(C₀-C₃ alkyl)-(C₅-C₁₀heteroaryl), wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl,aryl or heteroaryl group is independently optionally substituted.

In certain embodiments, R¹ is selected from the group consisting of—(C₆-C₁₀ aryl), and —(C₅-C₁₀ heteroaryl), wherein the aryl or heteroarylgroups is independently optionally substituted. In other embodiments,the aryl or heteroaryl group in R¹ is optionally substituted with atleast one selected from the group consisting of halo, C₁-C₆ alkyl,hydroxy, and C₁-C₆ alkoxy. In yet other embodiments, R¹ is phenyl orbenzo[d][1,3]dioxolyl.

In certain embodiments, R² is S(═O) or S(═O)₂. In other embodiments, R²is S(═O).

In certain embodiments, R³ is selected from the group consisting of—(C₆-C₁₀ aryl) and —(C₅-C₁₀ heteroaryl), wherein the aryl or heteroarylgroups is independently optionally substituted. In other embodiments, R³is naphthyl, benzyl or phenyl, wherein the naphthyl, benzyl or phenylgroup is optionally substituted. In yet other embodiments, the naphthyl,benzyl or phenyl group in R³ is optionally substituted with at least oneselected from the group consisting of halo, C₁-C₆ alkyl, hydroxy, andC₁-C₆ alkoxy.

In certain embodiments, R⁴ is —(CH₂)₁₋₃C(═O)NHR⁵. In other embodiments,R⁴ is —(CH₂)C(═O)NHR⁵.

In certain embodiments, R⁵ is selected from the group consisting of—C₁-C₆ alkyl, —(C₀-C₃ alkyl)-(C₃-C₈ cycloalkyl), —(C₀-C₃ alkyl)-(C₄-C₁₀heterocyclyl), —(C₀-C₃ alkyl)-(C₆-C₁₀ aryl), and —(C₀-C₃ alkyl)-(C₅-C₁₀heteroaryl), wherein the alkyl, cycloalkyl, heterocyclyl, aryl orheteroaryl groups is independently optionally substituted. In otherembodiments, R⁵ is —C₁-C₆ alkyl or —(C₃-C₈ cycloalkyl). In yet otherembodiments, the alkyl or cycloalkyl group in R⁵ is optionallysubstituted with at least one selected from the group consisting ofhalo, C₁-C₆ alkyl, hydroxy, and C₁-C₆ alkoxy.

In certain embodiments, the compound of formula (II) is:

N-(2-(cyclohexylamino)-2-oxoethyl)-2-((2-((4-fluorophenyl)amino)-2-oxoethyl)sulfinyl)-N-(naphthalen-1-yl)acetamide (KA494):

(N-cyclohexyl-N2-[({2-[(4-fluorophenyl)amino]-2-oxoethyl}sulfinyl)acetyl]-N²-1-naphthylglycinamide):

(N²-({[2-(1,3-benzodioxol-5-ylamino)-2-oxoethyl]sulfinyl}acetyl)-N²-(2-chlorobenzyl)-N-cyclopentylglycinamide)(KA680):

N-(2-(tert-butylamino)-2-oxoethyl)-2-((2-((4-fluorophenyl)amino)-2-oxoethyl)sulfinyl)-N-(m-tolyl)acetamide (KA381):

or a salt, tautomer or solvate thereof.

In one aspect, the compound is the compound of formula (III), or salt,tautomer or solvate thereof:

wherein in (III), each occurrence of R¹ is independently N or CR⁶; R² isselected from the group consisting of —(C₀-C₃ alkyl)-(C₄-C₁₀heterocyclyl), —(C₀-C₃ alkyl)-(C₆-C₁₀ aryl) and —(C₀-C₃ alkyl)-(C₅-C₁₀heteroaryl), wherein the alkyl, heterocyclyl, aryl or heteroaryl groupis independently optionally substituted; R³ and R⁴ are independentlyselected from the group consisting of —(CH₂)₁₋₃—C(═O)OR⁵,—(CH₂)₁₋₃—C(═O)NH₂, —(CH₂)₁₋₃—C(═O)NHR⁵, —S(CH₂)₁₋₃—C(═O)NH₂,—S(CH₂)₁₋₃—C(═O)OR⁵ and —S(CH₂)₁₋₃—C(═O)NHR⁵; each occurrence of R⁵ isindependently H, —C₁-C₆ alkyl, —C₃-C₁₀ cycloalkyl, —C₆-C₁₀ aryl, orheteroaryl, wherein the alkyl, cycloalkyl, aryl ord heteroaryl group isindependently optionally substituted; and each occurrence of R⁶ isindependently H, halo, —C₁-C₆ alkyl, —C₃-C₁₀ cycloalkyl, —C₆-C₁₀ aryl,or heteroaryl, wherein the alkyl, cycloalkyl, aryl or heteroaryl groupis independently optionally substituted.

In certain embodiments, each occurrence of R¹ is N.

In certain embodiments, R² is selected from the group consisting of—C₆-C₁₀ aryl and —C₅-C₁₀ heteroaryl.

In certain embodiments, R³ is selected from the group consisting of—S(CH₂)₁₋₃—C(═O)NH₂, —S(CH₂)₁₋₃—C(═O)OR⁵ and —S(CH₂)₁₋₃—C(═O)NHR⁵.

In certain embodiments, R⁴ is selected from the group consisting of—(CH₂)₁₋₃—C(═O)OR⁵, —(CH₂)₁₋₃—C(═O)NH₂, and —(CH₂)₁₋₃—C(═O)NHR⁵.

In certain embodiments, the compound of the invention is(2-[5-{[2-(cyclopentylamino)-2-oxoethyl]sulfanyl}-3-(4-pyridinyl)-1H-1,2,4-triazol-1-yl]-N-(3-methoxyphenyl)acetamide) (KA529), or a salt, tautomer or solvate thereof:

In one aspect, the compound is the compound of formula (IV), or salt,tautomer or solvate thereof:

wherein in (IV), R¹ is selected from the group consisting of —(C₀-C₃alkyl)-(C₄-C₁₀ heterocyclyl), —(C₀-C₃ alkyl)-(C₆-C₁₀ aryl) and —(C₀-C₃alkyl)-(C₅-C₁₀ heteroaryl), wherein the alkyl, heterocyclyl, aryl orheteroaryl group is independently optionally substituted; R² is selectedfrom the group consisting of —(CH₂)₁₋₃—C(═O)OR⁴, —(CH₂)₁₋₃—C(═O)NH₂, and—(CH₂)₁₋₃—C(═O)NHR⁴; R³ is —C(═O)OR⁴, —C(═O)NHR⁴ or —S(═O)₂NHR⁴; eachoccurrence of R⁴ is independently H, —C₁-C₆ alkyl, —C₃-C₁₀ cycloalkyl,—C₆-C₁₀ aryl, or heteroaryl, wherein the alkyl, cycloalkyl, aryl orheteroaryl group is independently optionally substituted; and A ring isoptionally further substituted.

In certain embodiments, R¹ is selected from the group consisting of—CH₂—(C₄-C₁₀ heterocyclyl), —CH₂—(C₆-C₁₀ aryl) and —CH₂—(C₅-C₁₀heteroaryl). In certain embodiments, R² is —(CH₂)₁₋₃—C(═O)NHR⁴. Incertain embodiments, R³ is —S(═O)₂NHR⁴. In certain embodiments, R³ ispara or meta to the —S(═O)₂NR¹R² group. In certain embodiments, R³ ispara to the —S(═O)₂NR¹R² group.

In certain embodiments, the compound of the invention isN²-(1,3-benzodioxol-5-ylmethyl)-N²-{[4-(cyclopentylsulfamoyl)phenyl]sulfonyl}-N-phenylglycinamide (KA199), or a salt, tautomer or solvate thereof:

In one aspect, the compound is the compound of formula (V), or salt,tautomer or solvate thereof:

wherein in (V), R¹ is selected from the group consisting of O, NH andN(C₁-C₆ alkyl), wherein the alkyl group is optionally substituted; R² isselected from the group consisting of H and —(C₁-C₆ alkyl), wherein thealkyl group is optionally substituted; R³ is selected from the groupconsisting of H, —(C₁-C₆ alkyl) and aryl, wherein the alkyl or arylgroup is optionally substituted; R⁴ is optionally substituted aryl; R⁵is selected from the group consisting of —CN, —C(═O)OH and —C(═O)O(C₁-C₆alkyl), wherein the alkyl group is optionally substituted; and R⁶ ismethyl or NH₂.

In certain embodiments, in (V) R¹ is O or NH.

In certain embodiments, in (V) R² is H or methyl.

In certain embodiments, in (V) R³ is H, methyl or phenyl, wherein themethyl or phenyl group is independently optionally substituted.

In certain embodiments, R⁴ is optionally substituted naphthyl oranthracenyl.

In certain embodiments, R⁵ is CN, —C(═O)OCH₃, —C(═O)OEt, or—C(═O)OCH₂CH₂OCH₃.

In certain embodiments, the compound of the invention is selected fromthe group consisting of:

2-amino-4-(2,7-diethoxynaphthalen-1-yl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile(KA092):

ethyl2-methyl-4-(naphthalen-1-yl)-5-oxo-7-phenyl-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate(KA031):

methyl7-(3,4-dimethoxyphenyl)-2-methyl-4-(naphthalen-1-yl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate(KA306):

2-methoxyethyl2-methyl-4-(naphthalen-1-yl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate(KA695):

methyl7-(4-methoxyphenyl)-2-methyl-4-(naphthalen-1-yl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate(KA819):

ethyl4-(anthracen-9-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate(KA820):

a salt, tautomer or solvate thereof, and any mixtures thereof.

In one aspect, the compound is the compound of formula (VI),3-(furan-2-ylmethyl)-8-(naphthalen-1-yl)-6-oxo-3,4,7,8-tetrahydro-2H,6H-pyrido[2,1-b][1,3,5]thiadiazine-9-carbonitrile(KA321), or salt, tautomer or solvate thereof:

In one aspect, the compound is the compound of formula (VII),6-amino-4-(2-hydroxynaphthalen-1-yl)-3-methyl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile(KA222), or salt, tautomer or solvate thereof:

In one aspect, the compound is the compound of formula (VIII),2-((3-cyano-4-(naphthalen-1-yl)-6-oxo-1,4,5,6-tetrahydropyridin-2-yl)thio)-N-phenylacetamide(KA095), or salt, tautomer or solvate thereof:

In one aspect, the compound is the compound of formula (IX), methyl6-amino-5-cyano-2-(methoxymethyl)-4-(naphthalen-1-yl)-4H-pyran-3-carboxylate(KA097), or salt, tautomer or solvate thereof:

In one aspect, the compound is the compound of formula (X),2-amino-4-(naphthalen-1-yl)-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-carbonitrile(KA290), or salt, tautomer or solvate thereof:

In one aspect, the compound is the compound of formula (XI), or salt,tautomer or solvate thereof:

wherein in (XI): each occurrence of R¹ is independently selected fromthe group consisting of H and methyl; R² is O or —NH; and R³ isoptionally substituted phenyl or naphthyl.

In certain embodiments, the compound of the invention is selected fromthe group consisting of:

1,3-dimethyl-5-(naphthalen-1-yl)-5,11-dihydro-1H-indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine-2,4,6(3H)-trione (KA811):

2-amino-5-(naphthalen-1-yl)-5,11-dihydro-1H-indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine-4,6-dione (KA592):

a salt, tautomer or solvate thereof, and any mixtures thereof.

In one aspect, the compound is the compound of formula (XII), or salt,tautomer or solvate thereof:

wherein in (XII): R¹ is phenyl or benzyl, wherein the phenyl or benzylgroup is optionally substituted; R² is H or methyl; and, R³ isoptionally substituted phenyl.

In certain embodiments, the compound of the invention is selected fromthe group consisting of:

3-(4-chlorophenyl)-7-(4-fluorophenyl)-3H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-c]pyrimidine (KA524):

3-(2-chlorobenzyl)-7-(4-fluorophenyl)-5-methyl-3H[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-c]pyrimidine (KA707):

7-(4-(1H-tetrazol-1-yl)phenyl)-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-c]pyrimidine (KA521):

a salt, tautomer or solvate thereof, and any mixtures thereof.

In one aspect, the compound is the compound of formula (XIII), or salt,tautomer or solvate thereof:

wherein in (XIII): R¹ is optionally substituted phenyl; R² is optionallysubstituted phenyl; and, R³ is optionally substituted phenyl orheteroaryl.

In certain embodiments, in (XIII) R³ is optionally substituted phenyl,optionally substituted pyridyl, optionally substituted quinolyl, oroptionally substituted isoquinolyl.

In certain embodiments, the compound of the invention is selected fromthe group consisting of:

4-(5-(4-butoxyphenyl)-4-phenyl-4H-1,2,4-triazol-3-yl)-2-(p-tolyl)quinolone(KA154):

4-(5-(4-(tert-butyl)phenyl)-4-(p-tolyl)-4H-1,2,4-triazol-3-yl)pyridine(KA261):

3-(5-(4-butoxyphenyl)-4-phenyl-4H-1,2,4-triazol-3-yl)aniline (KA774):

a salt, tautomer or solvate thereof, and any mixtures thereof.

The invention includes a pharmaceutical composition comprising at leastone pharmaceutically acceptable carrier and at least one compound of theinvention. In certain embodiments, the composition further comprises atleast one additional therapeutic agent.

The compounds of the invention may possess one or more stereocenters,and each stereocenter may exist independently in either the (R) or (S)configuration. In one embodiment, compounds described herein are presentin optically active or racemic forms. The compounds described hereinencompass racemic, optically-active, regioisomeric and stereoisomericforms, or combinations thereof that possess the therapeutically usefulproperties described herein. Preparation of optically active forms isachieved in any suitable manner, including by way of non-limitingexample, by resolution of the racemic form with recrystallizationtechniques, synthesis from optically-active starting materials, chiralsynthesis, or chromatographic separation using a chiral stationaryphase. In one embodiment, a mixture of one or more isomer is utilized asthe therapeutic compound described herein. In another embodiment,compounds described herein contain one or more chiral centers. Thesecompounds are prepared by any means, including stereoselectivesynthesis, enantioselective synthesis and/or separation of a mixture ofenantiomers and/or diastereomers. Resolution of compounds and isomersthereof is achieved by any means including, by way of non-limitingexample, chemical processes, enzymatic processes, fractionalcrystallization, distillation, and chromatography.

The methods and formulations described herein include the use ofN-oxides (if appropriate), crystalline forms (also known as polymorphs),solvates, amorphous phases, and/or pharmaceutically acceptable salts ofcompounds having the structure of any compound of the invention, as wellas metabolites and active metabolites of these compounds having the sametype of activity. Solvates include water, ether (e.g., tetrahydrofuran,methyl tert-butyl ether) or alcohol (e.g., ethanol) solvates, acetatesand the like. In one embodiment, the compounds described herein exist insolvated forms with pharmaceutically acceptable solvents such as water,and ethanol. In another embodiment, the compounds described herein existin unsolvated form. In one embodiment, the compounds of the inventionexist as tautomers. All tautomers are included within the scope of thecompounds recited herein.

In one embodiment, compounds described herein are prepared as prodrugs.A “prodrug” is an agent converted into the parent drug in vivo. In oneembodiment, upon in vivo administration, a prodrug is chemicallyconverted to the biologically, pharmaceutically or therapeuticallyactive form of the compound. In another embodiment, a prodrug isenzymatically metabolized by one or more steps or processes to thebiologically, pharmaceutically or therapeutically active form of thecompound.

In one embodiment, sites on, for example, the aromatic ring portion ofcompounds of the invention are susceptible to various metabolicreactions. Incorporation of appropriate substituents on the aromaticring structures may reduce, minimize or eliminate this metabolicpathway. In one embodiment, the appropriate substituent to decrease oreliminate the susceptibility of the aromatic ring to metabolic reactionsis, by way of example only, a deuterium, a halogen, or an alkyl group.

Compounds described herein also include isotopically-labeled compoundswherein one or more atoms is replaced by an atom having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number usually found in nature. Examples of isotopes suitablefor inclusion in the compounds described herein include and are notlimited to ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ³⁶Cl, ¹⁸F, ¹²³I, ¹²⁵I, ¹³N, ¹⁵N, ¹⁵O,¹⁷O, ¹⁸O, ³²P, and ³⁵S. In one embodiment, the isotope comprisesdeuterium. In certain embodiments, isotopically-labeled compounds areuseful in drug and/or substrate tissue distribution studies. In anotherembodiment, substitution with heavier isotopes such as deuterium affordsgreater metabolic stability (for example, increased in vivo half-life orreduced dosage requirements). In yet another embodiment, substitutionwith positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, isuseful in Positron Emission Topography (PET) studies for examiningsubstrate receptor occupancy. Isotopically-labeled compounds areprepared by any suitable method or by processes using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed. Isotopical labeling should not be construed to belimited to the compounds of the invention, but rather applies to thecompounds that may be used in combination with the compounds of theinvention, such as but not limited to acetazolamide, almitrine,theophylline, caffeine, methylprogesterone and related compounds,sedatives that increase arousal threshold in sleep disordered breathingpatients, benzodiazepine receptor agonists, orexin antagonists,tricyclic antidepressants, serotonergic modulators, adenosine andadenosine receptor and nucleoside transporter modulators, cannabinoids,orexins, melatonin agonists, ampakines, sodium oxybate, modafinil,armodafinil, and inhaled therapeutics. In certain embodiments, theoxybate salt is isotopically labeled with one or more deuteriums at theC-α position.

In one embodiment, the compounds described herein are labeled by othermeans, including, but not limited to, the use of chromophores orfluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Methods

The invention includes a method of treating an IL-1R-mediated disease ordisorder in a mammal in need thereof. The method comprises administeringto the mammal a therapeutically effective amount of at least onecompound of the invention, or a salt, tautomer or solvate thereof.

In certain embodiments, the compound of the invention is selected fromthe group consisting of: cyclohexyl2-((5-((2-((3-chlorophenyl)amino)thiazol-4yl)methyl)-4-(furan-2-ylmethyl)-4H-1,2,4-triazol-3-yl)thio)acetate;3-(4-(furan-2-ylmethyl)-5-(((2-(phenylamino)thiazol-4-yl)methyl)thio)-4H-1,2,4-triazol-3-yl)propanamide;ethyl2-(((4-(3-chlorophenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)methyl)thiazole-4-carboxylate;2-(((4-(3-chlorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl)thio)methyl)-N-(furan-2-ylmethyl)thiazole-4-carboxamide;N′-(2-((4-butyl-5-((2-((3-chlorophenyl)amino)thiazol-4-yl)methyl)-4H-1,2,4-triazol-3-yl)thio)acetyl)furan-2-carbohydrazide;2-((5-((2-((4-fluorophenyl)amino)thiazol-4-yl)methyl)-4-(furan-2-ylmethyl)-4H-1,2,4-triazol-3-yl)thio)acetamide;2-(((4-(3-chlorophenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)methyl)-N-cyclohexylthiazole-4-carboxamide;2-((4-allyl-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)-N-(benzo[d]thiazol-2-yl)acetamide;N-(4,5-dimethylthiazol-2-yl)-2-((4-ethyl-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)acetamide;2-((5-((2-((4-ethoxyphenyl)amino)thiazol-4-yl)methyl)-4-ethyl-4H-1,2,4-triazol-3-yl)thio)-N-(furan-2-ylmethyl)acetamide;N-(2-(cyclohexylamino)-2-oxoethyl)-2-((2-((4-fluorophenyl)amino)-2-oxoethyl)sulfinyl)-N-(naphthalen-1-yl)acetamide;(N-cyclohexyl-N2-[({2-[(4-fluorophenyl)amino]-2-oxoethyl}sulfinyl)acetyl]-N²-1-naphthylglycinamide);(N²-({[2-(1,3-benzodioxol-5-ylamino)-2-oxoethyl]sulfinyl}acetyl)-N²-(2-chlorobenzyl)-N-cyclopentylglycinamide);N-(2-(tert-butylamino)-2-oxoethyl)-2-((2-((4-fluorophenyl)amino)-2-oxoethyl)sulfinyl)-N-(m-tolyl)acetamide;(2-[5-{[2-(cyclopentylamino)-2-oxoethyl]sulfanyl}-3-(4-pyridinyl)-1H-1,2,4-triazol-1-yl]-N-(3-methoxyphenyl)acetamide);N²-(1,3-benzodioxol-5-ylmethyl)-N²-{[4-(cyclopentylsulfamoyl)phenyl]sulfonyl}-N-phenylglycinamide;2-amino-4-(2,7-diethoxynaphthalen-1-yl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile;ethyl2-methyl-4-(naphthalen-1-yl)-5-oxo-7-phenyl-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate;methyl7-(3,4-dimethoxyphenyl)-2-methyl-4-(naphthalen-1-yl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate;2-methoxyethyl2-methyl-4-(naphthalen-1-yl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate;methyl7-(4-methoxyphenyl)-2-methyl-4-(naphthalen-1-yl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate;ethyl4-(anthracen-9-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate(KA820);3-(furan-2-ylmethyl)-8-(naphthalen-1-yl)-6-oxo-3,4,7,8-tetrahydro-2H,6H-pyrido[2,1-b][1,3,5]thiadiazine-9-carbonitrile;6-amino-4-(2-hydroxynaphthalen-1-yl)-3-methyl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile;2-((3-cyano-4-(naphthalen-1-yl)-6-oxo-1,4,5,6-tetrahydropyridin-2-yl)thio)-N-phenylacetamide;methyl6-amino-5-cyano-2-(methoxymethyl)-4-(naphthalen-1-yl)-4H-pyran-3-carboxylate;2-amino-4-(naphthalen-1-yl)-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-carbonitrile;1,3-dimethyl-5-(naphthalen-1-yl)-5,11-dihydro-1H-indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine-2,4,6(3H)-trione;2-amino-5-(naphthalen-1-yl)-5,11-dihydro-1H-indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine-4,6-dione;3-(4-chlorophenyl)-7-(4-fluorophenyl)-3H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-c]pyrimidine;3-(2-chlorobenzyl)-7-(4-fluorophenyl)-5-methyl-3H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-c]pyrimidine;7-(4-(1H-tetrazol-1-yl)phenyl)-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-c]pyrimidine;4-(5-(4-butoxyphenyl)-4-phenyl-4H-1,2,4-triazol-3-yl)-2-(p-tolyl)quinolone;4-(5-(4-(tert-butyl)phenyl)-4-(p-tolyl)-4H-1,2,4-triazol-3-yl)pyridine;3-(5-(4-butoxyphenyl)-4-phenyl-4H-1,2,4-triazol-3-yl)aniline; a salt,tautomer or solvate thereof; and any mixtures thereof.

In certain embodiments, the compound is administered to the mammal aspart of a pharmaceutical composition. In other embodiments, the mammalis further administered at least one additional therapeutic agent. Inyet other embodiments, the compound and the at least one additionaltherapeutic agent are co-administered to the mammal. In yet otherembodiments, the compound and the at least one additional therapeuticagent are co-formulated. In yet other embodiments, the compound isadministered to the mammal a given period of time before or after the atleast one additional therapeutic agent is administered to the mammal. Inyet other embodiments, the mammal is human.

Combination Therapies

In one non-limiting embodiment, the compounds of the present inventionare useful in the methods of present invention in combination with oneor more additional compounds useful for treating a disease or disordercontemplated within the invention, such as but not limited to anIL-1R-mediated disease or disorder, such as but not limited toscleroderma, or a complication or symptom thereof. These additionalcompounds may comprise compounds of the present invention or othercompounds, e.g., commercially available compounds, known to treat,prevent, or reduce the symptoms of a disease or disorder contemplatedwithin the invention.

In non-limiting examples, the additional compounds comprises anakinra,rilonacept, azathioprine, methotrexate, bosentan, etanercept,halofuginone, iloprost, cyclophosphamide, cyclosporin A, mycophenolatemofetil, intravenous immunoglobulin, pirfenidone, prednisone, rituximab,beta-glycan peptides, basiliximab, sirolimus, alefacept, terguride,pomalidomide, and a tyrosine kinase inhibitor, such as imatinib,nilotinib or dasatinib.

A synergistic effect may be calculated, for example, using suitablemethods such as, for example, the Sigmoid-E_(max) equation (Holford &Scheiner, 19981, Clin. Pharmacokinet. 6: 429-453), the equation of Loeweadditivity (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114:313-326) and the median-effect equation (Chou & Talalay, 1984, Adv.Enzyme Regul. 22: 27-55). Each equation referred to above may be appliedto experimental data to generate a corresponding graph to aid inassessing the effects of the drug combination. The corresponding graphsassociated with the equations referred to above are theconcentration-effect curve, isobologram curve and combination indexcurve, respectively.

Administration/Dosage/Formulations

The regimen of administration may affect what constitutes an effectiveamount. The therapeutic formulations may be administered to the patienteither prior to or after the onset of an IL-1R-mediated disease ordisorder. Further, several divided dosages, as well as staggered dosagesmay be administered daily or sequentially, or the dose may becontinuously infused, or may be a bolus injection. Further, the dosagesof the therapeutic formulations may be proportionally increased ordecreased as indicated by the exigencies of the therapeutic orprophylactic situation.

Administration of the compositions of the present invention to apatient, preferably a mammal, more preferably a human, may be carriedout using known procedures, at dosages and for periods of time effectiveto treat an IL-1R-mediated disease or disorder in the patient. Aneffective amount of the therapeutic compound necessary to achieve atherapeutic effect may vary according to factors such as the state ofthe disease or disorder in the patient; the age, sex, and weight of thepatient; and the ability of the therapeutic compound to treat anIL-1R-mediated disease or disorder in the patient. Dosage regimens maybe adjusted to provide the optimum therapeutic response. For example,several divided doses may be administered daily or the dose may beproportionally reduced as indicated by the exigencies of the therapeuticsituation. A non-limiting example of an effective dose range for atherapeutic compound of the invention is from about 1 and 5,000 mg/kg ofbody weight/per day. One of ordinary skill in the art would be able tostudy the relevant factors and make the determination regarding theeffective amount of the therapeutic compound without undueexperimentation.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient that is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

In particular, the selected dosage level will depend upon a variety offactors including the activity of the particular compound employed, thetime of administration, the rate of excretion of the compound, theduration of the treatment, other drugs, compounds or materials used incombination with the compound, the age, sex, weight, condition, generalhealth and prior medical history of the patient being treated, and likefactors well, known in the medical arts.

A medical doctor, e.g., physician or veterinarian, having ordinary skillin the art may readily determine and prescribe the effective amount ofthe pharmaceutical composition required. For example, the physician orveterinarian could start doses of the compounds of the inventionemployed in the pharmaceutical composition at levels lower than thatrequired in order to achieve the desired therapeutic effect andgradually increase the dosage until the desired effect is achieved.

In particular embodiments, it is especially advantageous to formulatethe compound in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form as used herein refers tophysically discrete units suited as unitary dosages for the patients tobe treated; each unit containing a predetermined quantity of therapeuticcompound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical vehicle. The dosage unitforms of the invention are dictated by and directly dependent on (a) theunique characteristics of the therapeutic compound and the particulartherapeutic effect to be achieved, and (b) the limitations inherent inthe art of compounding/formulating such a therapeutic compound for thetreatment of an IL-1R-mediated disease or disorder in a patient.

In one embodiment, the compositions of the invention are formulatedusing one or more pharmaceutically acceptable excipients or carriers. Incertain embodiments, the pharmaceutical compositions of the inventioncomprise a therapeutically effective amount of a compound of theinvention and a pharmaceutically acceptable carrier.

The carrier may be a solvent or dispersion medium containing, forexample, water, ethanol, polyol (for example, glycerol, propyleneglycol, and liquid polyethylene glycol, and the like), suitable mixturesthereof, and vegetable oils. The proper fluidity may be maintained, forexample, by the use of a coating such as lecithin, by the maintenance ofthe required particle size in the case of dispersion and by the use ofsurfactants. Prevention of the action of microorganisms may be achievedby various antibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In manycases, it will be preferable to include isotonic agents, for example,sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol,in the composition. Prolonged absorption of the injectable compositionsmay be brought about by including in the composition an agent whichdelays absorption, for example, aluminum monostearate or gelatin.

In certain embodiments, the compositions of the invention areadministered to the patient in dosages that range from one to five timesper day or more. In other embodiments, the compositions of the inventionare administered to the patient in range of dosages that include, butare not limited to, once every day, every two, days, every three days toonce a week, and once every two weeks. It will be readily apparent toone skilled in the art that the frequency of administration of thevarious combination compositions of the invention will vary fromindividual to individual depending on many factors including, but notlimited to, age, disease or disorder to be treated, gender, overallhealth, and other factors. Thus, the invention should not be construedto be limited to any particular dosage regime and the precise dosage andcomposition to be administered to any patient will be determined by theattending physical taking all other factors about the patient intoaccount.

Compounds of the invention for administration may be in the range offrom about 1 μg to about 10,000 mg, about 20 μg to about 9,500 mg, about40 μg to about 9,000 mg, about 75 μg to about 8,500 mg, about 150 μg toabout 7,500 mg, about 200 μg to about 7,000 mg, about 3050 μg to about6,000 mg, about 500 μg to about 5,000 mg, about 750 μg to about 4,000mg, about 1 mg to about 3,000 mg, about 10 mg to about 2,500 mg, about20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 50 mg toabout 1,000 mg, about 75 mg to about 900 mg, about 100 mg to about 800mg, about 250 mg to about 750 mg, about 300 mg to about 600 mg, about400 mg to about 500 mg, and any and all whole or partial incrementstherebetween.

In some embodiments, the dose of a compound of the invention is fromabout 1 mg and about 2,500 mg. In some embodiments, a dose of a compoundof the invention used in compositions described herein is less thanabout 10,000 mg, or less than about 8,000 mg, or less than about 6,000mg, or less than about 5,000 mg, or less than about 3,000 mg, or lessthan about 2,000 mg, or less than about 1,000 mg, or less than about 500mg, or less than about 200 mg, or less than about 50 mg. Similarly, insome embodiments, a dose of a second compound (i.e., a drug used fortreating an IL-1R-mediated disease or disorder, or a complication orsymptom thereof) as described herein is less than about 1,000 mg, orless than about 800 mg, or less than about 600 mg, or less than about500 mg, or less than about 400 mg, or less than about 300 mg, or lessthan about 200 mg, or less than about 100 mg, or less than about 50 mg,or less than about 40 mg, or less than about 30 mg, or less than about25 mg, or less than about 20 mg, or less than about 15 mg, or less thanabout 10 mg, or less than about 5 mg, or less than about 2 mg, or lessthan about 1 mg, or less than about 0.5 mg, and any and all whole orpartial increments thereof.

In certain embodiments, the present invention is directed to a packagedpharmaceutical composition comprising a container holding atherapeutically effective amount of a compound of the invention, aloneor in combination with a second pharmaceutical agent; and instructionsfor using the compound to treat, prevent, or reduce one or more symptomsof an IL-1R-mediated disease or disorder in a patient.

Formulations may be employed in admixtures with conventional excipients,i.e., pharmaceutically acceptable organic or inorganic carriersubstances suitable for oral, parenteral, nasal, intravenous,subcutaneous, enteral, or any other suitable mode of administration,known to the art. The pharmaceutical preparations may be sterilized andif desired mixed with auxiliary agents, e.g., lubricants, preservatives,stabilizers, wetting agents, emulsifiers, salts for influencing osmoticpressure buffers, coloring, flavoring and/or aromatic substances and thelike. They may also be combined where desired with other active agents,e.g., other analgesic agents.

Routes of administration of any of the compositions of the inventioninclude nasal, inhalational, topical, oral, buccal, rectal, pleural,peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural,intratracheal, otic, intraocular, intrathecal and intravenous. Thecompounds for use in the invention may be formulated for administrationby any suitable route, such as for oral or parenteral, for example,transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal,(trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasaland (trans)rectal), intravesical, intrapulmonary, intraduodenal,intragastrical, intrathecal, subcutaneous, intramuscular, intradermal,intra-arterial, intravenous, intrabronchial, inhalation, and topicaladministration.

Suitable compositions and dosage forms include, for example, tablets,capsules, caplets, pills, gel caps, troches, dispersions, suspensions,solutions, syrups, granules, beads, transdermal patches, gels, powders,pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs,suppositories, liquid sprays for nasal or oral administration, drypowder or aerosolized formulations for inhalation, compositions andformulations for intravesical administration and the like. It should beunderstood that the formulations and compositions that would be usefulin the present invention are not limited to the particular formulationsand compositions that are described herein.

Oral Administration

For oral application, particularly suitable are tablets, dragees,liquids, drops, suppositories, or capsules, caplets and gelcaps. Thecompositions intended for oral use may be prepared according to anymethod known in the art and such compositions may contain one or moreagents selected from the group consisting of inert, non-toxicpharmaceutically excipients which are suitable for the manufacture oftablets. Such excipients include, for example an inert diluent such aslactose; granulating and disintegrating agents such as cornstarch;binding agents such as starch; and lubricating agents such as magnesiumstearate. The tablets may be uncoated or they may be coated by knowntechniques for elegance or to delay the release of the activeingredients. Formulations for oral use may also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertdiluent.

For oral administration, the compounds of the invention may be in theform of tablets or capsules prepared by conventional means withpharmaceutically acceptable excipients such as binding agents (e.g.,polyvinylpyrrolidone, hydroxypropylcellulose orhydroxypropylmethylcellulose); fillers (e.g., cornstarch, lactose,microcrystalline cellulose or calcium phosphate); lubricants (e.g.,magnesium stearate, talc, or silica); disintegrates (e.g., sodium starchglycollate); or wetting agents (e.g., sodium lauryl sulphate). Ifdesired, the tablets may be coated using suitable methods and coatingmaterials such as OPADRY™ film coating systems available from Colorcon,West Point, Pa. (e.g., OPADRY™ OY Type, OYC Type, Organic Enteric OY-PType, Aqueous Enteric OY-A Type, OY-PM Type and OPADRY™ White,32K18400). Liquid preparation for oral administration may be in the formof solutions, syrups or suspensions. The liquid preparations may beprepared by conventional means with pharmaceutically acceptableadditives such as suspending agents (e.g., sorbitol syrup, methylcellulose or hydrogenated edible fats); emulsifying agent (e.g.,lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily estersor ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).

Granulating techniques are well known in the pharmaceutical art formodifying starting powders or other particulate materials of an activeingredient. The powders are typically mixed with a binder material intolarger permanent free-flowing agglomerates or granules referred to as a“granulation.” For example, solvent-using “wet” granulation processesare generally characterized in that the powders are combined with abinder material and moistened with water or an organic solvent underconditions resulting in the formation of a wet granulated mass fromwhich the solvent must then be evaporated.

Melt granulation generally consists in the use of materials that aresolid or semi-solid at room temperature (i.e. having a relatively lowsoftening or melting point range) to promote granulation of powdered orother materials, essentially in the absence of added water or otherliquid solvents. The low melting solids, when heated to a temperature inthe melting point range, liquefy to act as a binder or granulatingmedium. The liquefied solid spreads itself over the surface of powderedmaterials with which it is contacted, and on cooling, forms a solidgranulated mass in which the initial materials are bound together. Theresulting melt granulation may then be provided to a tablet press or beencapsulated for preparing the oral dosage form. Melt granulationimproves the dissolution rate and bioavailability of an active (i.e.drug) by forming a solid dispersion or solid solution.

U.S. Pat. No. 5,169,645 discloses directly compressible wax-containinggranules having improved flow properties. The granules are obtained whenwaxes are admixed in the melt with certain flow improving additives,followed by cooling and granulation of the admixture. In certainembodiments, only the wax itself melts in the melt combination of thewax(es) and additives(s), and in other cases both the wax(es) and theadditives(s) will melt.

The present invention also includes a multi-layer tablet comprising alayer providing for the delayed release of one or more compounds of theinvention, and a further layer providing for the immediate release of amedication for treatment of an IL-1R-mediated disease or disorder. Usinga wax/pH-sensitive polymer mix, a gastric insoluble composition may beobtained in which the active ingredient is entrapped, ensuring itsdelayed release.

Parenteral Administration

For parenteral administration, the compounds of the invention may beformulated for injection or infusion, for example, intravenous,intramuscular or subcutaneous injection or infusion, or foradministration in a bolus dose and/or continuous infusion. Suspensions,solutions or emulsions in an oily or aqueous vehicle, optionallycontaining other formulatory agents such as suspending, stabilizingand/or dispersing agents may be used.

Additional Administration Forms

Additional dosage forms of this invention include dosage forms asdescribed in U.S. Pat. Nos. 6,340,475, 6,488,962, 6,451,808, 5,972,389,5,582,837, and 5,007,790. Additional dosage forms of this invention alsoinclude dosage forms as described in U.S. Patent Applications Nos.20030147952, 20030104062, 20030104053, 20030044466, 20030039688, and20020051820. Additional dosage forms of this invention also includedosage forms as described in PCT Applications Nos. WO 03/35041, WO03/35040, WO 03/35029, WO 03/35177, WO 03/35039, WO 02/96404, WO02/32416, WO 01/97783, WO 01/56544, WO 01/32217, WO 98/55107, WO98/11879, WO 97/47285, WO 93/18755, and WO 90/11757.

Controlled Release Formulations and Drug Delivery Systems

In certain embodiments, the formulations of the present invention maybe, but are not limited to, short-term, rapid-offset, as well ascontrolled, for example, sustained release, delayed release andpulsatile release formulations.

The term sustained release is used in its conventional sense to refer toa drug formulation that provides for gradual release of a drug over anextended period of time, and that may, although not necessarily, resultin substantially constant blood levels of a drug over an extended timeperiod. The period of time may be as long as a month or more and shouldbe a release which is longer that the same amount of agent administeredin bolus form.

For sustained release, the compounds may be formulated with a suitablepolymer or hydrophobic material which provides sustained releaseproperties to the compounds. As such, the compounds for use the methodof the invention may be administered in the form of microparticles, forexample, by injection or in the form of wafers or discs by implantation.

In a preferred embodiment of the invention, the compounds of theinvention are administered to a patient, alone or in combination withanother pharmaceutical agent, using a sustained release formulation.

The term delayed release is used herein in its conventional sense torefer to a drug formulation that provides for an initial release of thedrug after some delay following drug administration and that mat,although not necessarily, includes a delay of from about 10 minutes upto about 12 hours.

The term pulsatile release is used herein in its conventional sense torefer to a drug formulation that provides release of the drug in such away as to produce pulsed plasma profiles of the drug after drugadministration.

The term immediate release is used in its conventional sense to refer toa drug formulation that provides for release of the drug immediatelyafter drug administration.

As used herein, short-term refers to any period of time up to andincluding about 8 hours, about 7 hours, about 6 hours, about 5 hours,about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40minutes, about 20 minutes, or about 10 minutes and any or all whole orpartial increments thereof after drug administration after drugadministration.

As used herein, rapid-offset refers to any period of time up to andincluding about 8 hours, about 7 hours, about 6 hours, about 5 hours,about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40minutes, about 20 minutes, or about 10 minutes, and any and all whole orpartial increments thereof after drug administration.

Dosing

The therapeutically effective amount or dose of a compound of thepresent invention will depend on the age, sex and weight of the patient,the current medical condition of the patient and the progression of anIL-1R-mediated disease or disorder in the patient being treated. Theskilled artisan will be able to determine appropriate dosages dependingon these and other factors.

A suitable dose of a compound of the present invention may be in therange of from about 0.01 mg to about 5,000 mg per day, such as fromabout 0.1 mg to about 1,000 mg, for example, from about 1 mg to about500 mg, such as about 5 mg to about 250 mg per day. The dose may beadministered in a single dosage or in multiple dosages, for example from1 to 4 or more times per day. When multiple dosages are used, the amountof each dosage may be the same or different. For example, a dose of 1 mgper day may be administered as two 0.5 mg doses, with about a 12-hourinterval between doses.

It is understood that the amount of compound dosed per day may beadministered, in non-limiting examples, every day, every other day,every 2 days, every 3 days, every 4 days, or every 5 days. For example,with every other day administration, a 5 mg per day dose may beinitiated on Monday with a first subsequent 5 mg per day doseadministered on Wednesday, a second subsequent 5 mg per day doseadministered on Friday, and so on.

The compounds for use in the method of the invention may be formulatedin unit dosage form. The term “unit dosage form” refers to physicallydiscrete units suitable as unitary dosage for patients undergoingtreatment, with each unit containing a predetermined quantity of activematerial calculated to produce the desired therapeutic effect,optionally in association with a suitable pharmaceutical carrier. Theunit dosage form may be for a single daily dose or one of multiple dailydoses (e.g., about 1 to 4 or more times per day). When multiple dailydoses are used, the unit dosage form may be the same or different foreach dose.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, numerous equivalents to thespecific procedures, embodiments, claims, and examples described herein.Such equivalents were considered to be within the scope of thisinvention and covered by the claims appended hereto. For example, itshould be understood, that modifications in reaction conditions,including but not limited to reaction times, reaction size/volume, andexperimental reagents, such as solvents, catalysts, pressures,atmospheric conditions, e.g., nitrogen atmosphere, andreducing/oxidizing agents, with art-recognized alternatives and using nomore than routine experimentation, are within the scope of the presentapplication.

It is to be understood that wherever values and ranges are providedherein, all values and ranges encompassed by these values and ranges,are meant to be encompassed within the scope of the present invention.Moreover, all values that fall within these ranges, as well as the upperor lower limits of a range of values, are also contemplated by thepresent application.

The following examples further illustrate aspects of the presentinvention. However, they are in no way a limitation of the teachings ordisclosure of the present invention as set forth herein.

EXAMPLES

The invention is now described with reference to the following Examples.These Examples are provided for the purpose of illustration only, andthe invention is not limited to these Examples, but rather encompassesall variations that are evident as a result of the teachings providedherein.

Example 1: Screening Studies

A hybrid structure based screening method was used to design smallmolecule inhibitors of IL-1R that bind at the antagonist site. Using the21 amino acid peptide complexed IL-1R crystal structure as a template, afour point hybrid pharmacophore was designed and screened against alibrary of 3 million small molecules. The resulting 662 hits werefiltered for drug-like properties, and 230 hits that cleared thefiltering schemes were docked to the well-prepared IL-1R proteinantagonist binding site using the molecular docking program—GOLD(version 4.1).

The docked protein-ligand complexes were ranked using customized scoringschemes and five high ranking compounds (KA199, KA494, KA529, KA680, andKA862) were selected for in vitro validation. Molecular docking studiesrevealed that the compounds bind to the same site as the antagonistpeptide or endogenous protein and hence can block the interaction ofIL-1 with the IL-1R (FIG. 1).

Example 2: Collagen Synthesis

SSc fibroblasts were cultured with selected molecules of the invention,and total collagen synthesis was assessed with hydroxyproline. Fourcompounds demonstrated efficacy at 10 mM (FIG. 5). KA862 and KA494 wereselected for further in vitro evaluation.

Example 3: Blockage of IL-1 Signaling

FIG. 6 illustrates the finding that compounds of the invention directlyblocks IL-1 signaling in normal fibroblasts.

Example 4: Bleomycin Induced Fibrosis

FIG. 7 illustrates the finding that compounds of the invention areeffective against bleomycin induced fibrosis. Normal fibroblasts weretreated with bleomycin and either IL-1RA or a compound of the invention,so as to inhibit collagen.

Example 5: Bleomycin Mouse Model of Fibrosis

The bleomycin mouse model of fibrosis is a well-established model forthe study of initiating events of fibrosis in scleroderma.Substantively, fibrosis is induced with bleomycin in C57BL/6J mice. Skinfibrosis is induced by intradermal injections of bleomycin. Compounds ofthe invention, or vehicle, are administered daily by injecting thecompounds or an equivalent volume of saline intraperitoneally. At theend of the study, mice are humanely euthanized, and lung, spleen, anddorsal skin, including tissue surrounding the bleomycin injection site,are harvested from each animal. Skin and lung are analyzed for fibrosisby histology, and spleen for inflammatory cells by flow cytometry. Oraladministration of the compounds of the invention in this model is alsoevaluated.

Example 6

Compounds of the invention were analyzed to determine whether they wereeffective at preventing bleomycin induced fibrosis. Four compounds(KA521, KA222, KA306 and KA695) were selected for further testing anddevelopment. The experimental IC₅₀ for KA222, KA306 and KA695 wasdetermined to be around 1 nM (FIG. 9).

Example 7

Three exemplary compounds of the invention were found to abrogatecollagen synthesis by SSc fibroblasts at 1 nM (FIG. 10). The testedcompounds significantly ameliorated collagen levels and returnedcollagen synthesis to nearly normal levels.

The disclosures of each and every patent, patent application, andpublication cited herein are hereby incorporated herein by reference intheir entirety. While this invention has been disclosed with referenceto specific embodiments, it is apparent that other embodiments andvariations of this invention may be devised by others skilled in the artwithout departing from the true spirit and scope of the invention. Theappended claims are intended to be construed to include all suchembodiments and equivalent variations.

What is claimed is:
 1. A method of relieving or improving anIL-1R-mediated disease or disorder in a mammal, wherein theIL-1R-mediated disease or disorder is scleroderma or systemic lupuserythematosus (lupus), the method comprising administering to the mammala therapeutically effective amount of at least one compound, or a salt,tautomer or solvate thereof, wherein the at least one compound is acompound of formula (XI):

wherein in (XI): each occurrence of R¹ is independently selected fromthe group consisting of H and methyl; R² is O or —NH; and R³ isoptionally substituted phenyl or naphthyl.
 2. The method of claim 1,wherein the compound is selected from the group consisting of1,3-dimethyl-5-(naphthalen-1-yl)-5,11-dihydro-1H-indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine-2,4,6(3H)-trione;and2-amino-5-(naphthalen-1-yl)-5,11-dihydro-1H-indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine-4,6-dione;or a salt, tautomer or solvate thereof.
 3. The method of claim 1,wherein the mammal is further administered at least one therapeuticagent.
 4. The method of claim 3, wherein the therapeutic agent comprisesat least one selected from the group consisting of anakinra, rilonacept,azathioprine, methotrexate, bosentan, etanercept, halofuginone,iloprost, cyclophosphamide, cyclosporin A, mycophenolate mofetil,intravenous immunoglobulin, pirfenidone, prednisone, rituximab,beta-glycan peptides, basiliximab, sirolimus, alefacept, terguride,pomalidomide, and a tyrosine kinase inhibitor.
 5. The method of claim 3,wherein the compound and the therapeutic agent are co-administered tothe mammal.
 6. The method of claim 3, wherein the compound isadministered to the mammal in a given period of time before or after thetherapeutic agent is administered to the mammal.
 7. The method of claim1, wherein the compound is formulated as a pharmaceutical composition.8. The method of claim 1, wherein the mammal is human.